Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)[C:5]#[N:6])([CH3:3])[CH3:2].[NH2-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>C1(C)C=CC=CC=1>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:4]([CH:1]([CH3:3])[CH3:2])([CH2:20][CH2:21][CH2:22][Cl:23])[C:5]#[N:6])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: ClCCCBr
Reactant: COc1ccc(C(C#N)C(C)C)cc1OC
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(C#N)(CCCCl)C(C)C)cc1OC
Temperature: 15 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3,4-dimethoxyphenyl)-2-isopropylacetonitrile (6a) in toluene is slowly added to sodium amide (1.5 eq) in toluene, and the resulting mixture warmed to 80°-90° C. for one hour. The mixture was then cooled to 15° C. and 1-bromo-3-chloropropane (2 eq) slowly added and stirred for two hours at room temperature. The mixture is then carefully poured into ice water, extracted with CH2Cl2, and vacuum distilled to yield 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-chloropropyl)acetonitrile (21, b.p. 160°-165°/0.05 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:21][OH:22])=[NH:15])[CH:11]=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#Cc1cc(C(F)(F)F)cc(-c2ccc(Cl)cc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(NO)c1cc(C(F)(F)F)cc(-c2ccc(Cl)cc2)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 86.3 %

Procedure:
A mixture of 6-(4-chloro-phenyl)-4-trifluoromethyl-pyridine-2-carbonitrile (example B.5) (3.6 g, 13 mmol), hydroxylamine-hydrochloride (3.275 g, 47 mmol) and sodium carbonate (2.7 g, 47 mmol) in EtOH (60 ml) and water (60 ml) was stirred under argon atmosphere at 100° C. for 4 h. The EtOH was evaporated, the mixture was diluted with water and stirred for 1 h at 0° C. The crude product was filtered and dried in HV to give the pure title compound as a light yellow solid (3.54 g, 88%). MS (ISP) 316.1 [(M+H)+] and 318 [(M+2+H)+]; mp 180-186° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[Cl-]>O>[NH2:2][C:3]1[N:8]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=[O:11])[C:6]([Cl:1])=[CH:5][CH:4]=1
Reactant: CON=C(C(=O)O)c1cccc(N)n1
Reactant: Cl
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Product: CON=C(C(=O)O)c1nc(N)ccc1Cl

Procedure:
To a mixture of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (syn isomer), acetic acid (350 ml.) and water (10 ml.) was introduced chloride gas for 1.5 hours. After the removal of the excess of the chlorine gas by bubbling air into the reaction mixture, the solvent was distilled off. The residue was pulverized in diethyl ether and collected by filtration. After the addition of water and ethyl acetate to the resultant powder (9.8 g.), the aqueous layer was separated and washed with ethyl acetate. The ethyl acetate layer and washings were combined together, and further extracted with water. The aqueous layers were combined together and adjusted to pH 4 with 1N aqueous solution of sodium hydroxide, and then the solvent was distilled off under reduced pressure. The remaining water in the residue was azeotropically removed with benzene three times to yield brownish powder which was dried in a desiccator to give 2-(6-amino-3-chloropyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (3.27 g.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].[C:14]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:27][CH:26]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Solvent: c1ccncc1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2,4-dimethylphenyl)(2-methylpropyl)amine (1.00 g, 5.64 mmol) in pyridine (20 mL) was added 4-[(phenylmethyl)oxy]benzenesulfonyl chloride (1.754 g, 6.20 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo then redissolved in ethyl acetate and washed with a 10% solution of citric acid. At this stage a white precipitate formed and was isolated by filtration, LCMS analysis confirmed the precipitate was the desired product. The organic phase was then washed with 2 M NaOH and further precipitate was collected, again confirmed as the desired product by LCMS analysis. The organic phase was dried with magnesium sulfate, concentrated in vacuo and treated with dichloromethane to give a cloudy suspension, which was filtered to provide more of the desired product. Finally the filtrate was concentrated in vacuo and treated with methanol, whereupon additional product crystallised from the solution. The collected batches of product were combined (974 mg, 2.300 mmol) and used without further purification in the next step. LCMS [LCMS1] Rt 1.54 min, m/z (ES+) 424 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[F:12].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][OH:20].[H-].[Na+]>CS(C)=O>[F:12][C:3]1[CH:4]=[C:5]2[CH:10]=[CH:9][N:8]([CH3:11])[C:6]2=[N:7][C:2]=1[O:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: Cn1ccc2cc(F)c(Cl)nc21
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1ccc2cc(F)c(OCc3ccccn3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a stirred solution of 6-chloro-5-fluoro-1-methyl-1H-pyrrolo[2,3-b]pyridine (1.276 g, 6.91 mmol) and 2-pyridine methanol (0.800 mL, 8.29 mmol) in dimethyl sulphoxide (10 mL), under a nitrogen atmosphere, is added 60% sodium hydride (0.332 g, 8.29 mmol) portionwise, and reaction stirred at room temperature overnight. The reaction is then heated to 80° C. for 1 h, cooled to room temperature and further 60% sodium hydride (0.090 g, 2.32 mmol) added. After 30 minutes of stirring at room temperature, the reaction is further heated at 80° C. for 30 minutes. The reaction is cooled, poured onto brine (ca. 50 mL) and the product extracted with CHCl3 (ca. 2×30 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown oil. This is purified by column chromatography on silica, eluting with 0 to 80% EtOAc in hexane, to give the title compound as a light green oil (1.445 g, 5.62 mmol). MS (m/z): 258 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:9](F)=[N:8][CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5].[NH2:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1>C(OCC)(=O)C>[Cl:1][C:2]1[C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[N:8][CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5]
Reactant: Cc1ccccc1N
Reactant: N#Cc1c(Cl)cnc(F)c1Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1Nc1ncc(Cl)c(C#N)c1Cl
Temperature: 150 °C
Yield: 75.5 %

Procedure:
A mixture of 3,5-dichloro-2-fluoroisonicotinonitrile (1.00 g, 5.24 mmol) and o-toluidine (10 g, 93 mmol) was heated to 150° C. for 20 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (200 mL), washed with 1 N HCl (2×20 mL), saturated sodium bicarbonate (20 mL), and brine (20 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane-hexanes (1:1) and eluting with 0 to 20% ethyl acetate in hexanes, gave 3,5-dichloro-2-(o-tolylamino)isonicotinonitrile as yellow solid (1.10 g, 76% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.18 (1H, s), 7.71 (1H, δ, J=7.78 Hz), 7.23-7.40 (2H, m), 7.01-7.13 (1H, m), 6.70-6.94 (1H, m), 2.29 (3H, s); MS (ES+) m/z: 278 (M+H); LC retention time: 3.68 min (analytical HPLC Method A).
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][C:5]1=[O:16])(=[O:3])[CH3:2].[H][H]>ClCCl.CO.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1C(=O)Cc2cc(N)ccc21

Procedure:
30.0 g (136 mmol) of 1-acetyl-5-nitro-2-indolinone are dissolved in a mixture of 650 ml of dichloromethane and 650 ml of methanol and after the addition of 5 g of 10% palladium on activated charcoal the mixture is hydrogenated for 45 minutes with hydrogen. Then the catalyst is filtered off and evaporated down.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.O1CCOCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([NH:1][C:2]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:22][CH:21]=1
Reactant: Fc1ccc(I)cc1
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Oc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 51.5 %

Procedure:
To dioxane 5.0 mL solution of methyl 2-amino-4-phenoxybenzoate 0.34 g were added 1-fluoro-4-iodobenzene 0.18 mL,1,1′-bis(diphenylphosphino)ferrocene 93 mg,1,1′-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex 46 mg and sodium tert-butoxide 0.15 g at room temperature, and it was heated and refluxed under nitrogen atmosphere for 3 hours. After the reaction mixture was cooled to room temperature,10% citric acid aqueous solution and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to give methyl 2-(4-fluoroanilino)-4-phenoxybenzoate 0.036 g of colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1C(=O)CCC1.CCN=C=NCCCN(C)C.[NH:42]1[CH2:47][CH2:46][S:45][CH2:44][CH2:43]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH3:13])[C:10](=[O:12])[N:42]1[CH2:47][CH2:46][S:45][CH2:44][CH2:43]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: C1CSCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)C(=O)N1CCSCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 2-tert-Butoxycarbonylamino-propionic acid (3.5 g, 18.5 mmol), HOBt (22.2 mmol), NMP (22.2 mmol) and EDCI (22.2 mmol) in CH2Cl2 was added thiomorpholine (2.29 g, 22.2 mmol) at 0° C. The reaction mixture was stirred at 0° C. overnight, then washed with 2% aqueous NaOH, water, brine, and dried over Na2SO4. The solvent was removed under vacuum to give (1-Methyl-2-oxo-2-thiomorpholin-4-yl -ethyl)-carbamic acid tert-butyl ester (5.0 g) yield 98%. MS (M+H)=275.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][N:41]=[C:40]2[S:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:53][C:52]2[CH:54]=[CH:55][CH:56]=[C:50]([S:49][C:40]3[C:39]4[C:44](=[CH:45][C:46]([O:47][CH3:48])=[C:37]([O:36][CH3:35])[CH:38]=4)[N:43]=[CH:42][N:41]=3)[CH:51]=2)=[O:19])[N:7]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(C2CCCCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4C4CCCCC4)c3)c2cc1OC
Temperature: 60 °C
Yield: 18 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate prepared as described in Example 330A (200 mg, 0.59 mmol), N,N-diisopropylethylamine (67 mg, 0.52 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (85 mg, 0.27 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane:methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (52 mg, 18%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.71 (s, 1H), 8.53 (s, 1H), 7.84 (s, 1H), 7.26-7.55 (m, 5H), 6.06 (s, 1H), 4.00 (s, 6H), 3.94 (m, 1H), 1.62-1.81 (m, 7H), 1.24-1.36 (m, 12H); LC-MS (ESI) m/z 561 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:26])[C:9](OS(C(F)(F)F)(=O)=O)=[N:10]2)=[CH:5][C:4]=1[C:27]([O:29][CH3:30])=[O:28].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:9]2[C:8]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:26])=[N:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([C:27]([O:29][CH3:30])=[O:28])[CH:5]=3)[N:10]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(OS(=O)(=O)C(F)(F)F)nc2cc1OC
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc2nc(N3CCC[C@@H]3C)c(-c3ccc(F)cc3)nc2cc1OC
Temperature: 95 °C
Reaction time: 0.67 h
Yield: 75.8 %

Procedure:
To a solution of (S)-methyl 7-methoxy-3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (300 mg, crude) in dioxane (5 ml) and water (3 drops) was added (4-fluorophenyl)boronic acid (280.6 mg, 2.01 mmol), Pd(PPh3)4 (38.5 mg, 0.03 mmol), and K3PO4 (422 mg, 1.99 mmol), and the reaction was stirred for 40 minutes at 95° C. under an atmosphere of nitrogen. The reaction mixture was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(4-fluorophenyl)-7-methoxy-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a light yellow solid (200 mg).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.C[N:31](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][N:2]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=[O:22])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:31])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CN(C)C=O
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a mixture of 2-{7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (72 mg) obtained in Example 336, 1H-1,2,3-benzotriazol-1-ol-ammonia complex (40 mg) and N,N-dimethylformamide (3 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (50 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hours. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (57 mg, yield: 79%) as pale-yellow prism crystals. MS: 430 (MH+). melting point 148-149° C.
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:23])=[C:11]([C:16]2[N:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=2)[CH:12]=[CH:13][C:14]=1[CH3:15])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[NH2:22][C:19]1[N:20]=[CH:21][C:16]([C:11]2[C:10]([F:23])=[C:9]([OH:8])[C:14]([CH3:15])=[CH:13][CH:12]=2)=[N:17][CH:18]=1
Reactant: Cc1ccc(-c2cnc(N)cn2)c(F)c1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cnc(N)cn2)c(F)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(3-((tert-Butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)pyrazin-2-amine (342 mg, 1.03 mmol) was dissolved in THF (1.2 mL) at rt and then treated with tetrabutylammonium fluoride (1.2 mL, 1 M in THF). The reaction was stirred for 1 hour at rt, before diluting with water (10 mL) and extracting with EtOAc (10 mL×4). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by FCC to provide the title compound. 1H NMR (500 MHz, CD3OD) δ 8.26 (dd, J=2.3, 1.5, 1H), 8.01 (d, J=1.5, 1H), 7.09 (m, 1H), 6.94 (m, 1H), 2.25 (s, 3H).
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].[N+:27]([C:30]1[CH:65]=[CH:64][C:33]([CH2:34][O:35][C:36]([NH:38][CH2:39][CH2:40][CH2:41][S:42][C:43]2[N:44]=[CH:45][N:46]3[CH:50]=[C:49]([Sn](CCCC)(CCCC)CCCC)[S:48][C:47]=23)=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[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:49]3[S:48][C:47]4=[C:43]([S:42][CH2:41][CH2:40][CH2:39][NH:38][C:36]([O:35][CH2:34][C:33]5[CH:64]=[CH:65][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=5)=[O:37])[N:44]=[CH:45][N:46]4[CH:50]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)c2s1
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
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCCCNC(=O)OCc5ccc([N+](=O)[O-])cc5)c4s3)[C@H](C)[C@H]12
Yield: 63.6 %

Procedure:
The procedure of Example 1a) was repeated, except that 628 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.24 g of 7-[3-(4-nitrobenzyloxycarbonyl)aminopropyl]thio-2-(tri-n-butylstannyl)imidazo[5,1-b]-thiazole were used as the starting compounds. Thus, 812 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-[3-(4-nitrobenzyloxycarbonyl)aminopropyl]thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate were prepared.
Reaction SMILES: Cl.[C:2]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[C:9]=1[Cl:10])([OH:4])=O.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[NH2:35])=[N:24][CH:25]=1>S(Cl)(Cl)=O.N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=2[NH:35][C:2]([C:5]2[S:6][CH:7]=[C:8]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[C:9]=2[Cl:10])=[O:4])=[N:24][CH:25]=1
Reactant: CN1CCN(Cc2csc(C(=O)O)c2Cl)CC1
Reactant: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CN1CCN(Cc2csc(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)c2Cl)CC1
Temperature: 25 °C
Reaction time: 90 h
Yield: 78.5 %

Procedure:
A suspension of 2-carboxy-3-chloro-4-(4-methylpiperazin-1-yl)methylthiophene HCl salt (2.0 g, 5.8 mmol) in thionyl chloride (50 mL) was heated at reflux. After 90 hours, the mixture was cooled to ambient temperature and concentrated of all volatiles in vacuo. To a suspension of the resulting solid in pyridine (20 mL) at 0° C was added N-(5-chloropyridin-2-yl)-2-amino-5-chlorobenzamide (1.5 g, 5.2 mmol) in pyridine (5 mL). The mixture was stirred and allowed to warm gradually to ambient temperature. After 16 hours, the mixture was concentrated of all volatiles in vacuo. Purification by flash chromatography on silica gel afforded 2.2 g (80% yield) of N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide, as a tan foam; NMR (DMSO-d6 /TFA) 11.4 (s, 1), 11.0 (s, 1), 7.6-8.4 (m, 7), 4.4 (s, 2), 3.04.0 (br m, 8), 2.9 (s, 3) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:10]=1[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[C:10]=1[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCO[Si](C)(C)C(C)(C)C)c1CCC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1cccc(CCCCCCO)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 4-[3-[6-(tert-butyl-dimethyl-silanyloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (0.837 mmol, 438 mg) in THF (12 mL) was added a solution of n-tetrabutyl ammonium fluoride (1.25 mmol, 1.25 mL, 1.0M) in THF at 0° C. Then, the resulting colorless solution was allowed to warm to room temperature in 2 h and the mixture was stirred for another 2 h at room temperature before being diluted with water (˜50 mL). The organic compound was extracted into ethyl acetate (2×50 mL) and the combined extracts were washed with brine solution (100 mL). The organic solution was dried over anhydrous magnesium sulfate and the filtrate was removed under vacuum after filtration of the drying agent. The crude residue was dried further under high vacuum and the desired 4-[2-(2-ethoxycarbonyl-ethyl)-3-(6-hydroxy-hexyl)-phenoxy]-butyric acid ethyl ester (342 mg, 99%) was isolated as a colorless oil: ES(+)-HRMS m/e calculated for C23H36O6 (M+Na)+ 431.2404, found 431.2404.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([O:15]CC)=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1.CO.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)O)cnc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step C (399 mg, mmol) in THF (6 mL) was added methanol (1 mL) followed by NaOH (5N, 1.5 mL). After stirring at room temperature for 18 hours the reaction was concentrated in vacuo. The residue was acidified with 1N HCl (10 mL). The solution was concentrated in vacuo and azeotroped with toluene (4×). This material was used in the next step without any further purification.