Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][NH2:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[CH:25]=O)(=[O:21])=[O:20])=[CH:15][CH:14]=1>CCO.C(O)(=O)C>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH2:22][C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2/[CH:25]=[N:11]/[NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cc2ccccc2C=O)cc1
Reactant: NNC(=O)Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)Cc2ccccc2/C=N/NC(=O)Cc2ccccc2)cc1
Reaction time: 2.5 h
Yield: 78 %

Procedure:
To a solution of-phenylacetic acid hydrazide (0.24 mmol) in absolute EtOH 10 mL and acetic acid 0.4 mL is added 2-{[(4-methylphenyl)sulfonyl]methyl}benzaldehyde (0.22 mmol). The reaction is stirred at room temperate for 2.5 hr with white ppt formation. The reaction mixture is then filtered. The solid is triturated with MeOH to give N′-[(1E)-(2-{[(4-methylphenyl)sulfonyl]methyl}phenyl)methylene]-2-phenylacetohydrazide in 78% yield. 1H NMR (400 MHz, DMSO-d6) □ 11.50–11.25 (2s, 1H), 8.22–8.13 (2s, 1H), 7.79 (m, 1H), 7.56 (m, 2H), 7.31 (m, 10H), 4.93–4.80 (2s, 2H), 3.95–3.57 (2s, 2H), 2.36–2.31 (2s, 3H). ESI− for C23H22N2O3S, m/z 405 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([F:26])[C:5]2[N:6]([C:8]([C:11]([F:25])([F:24])[C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][C:16]([O:22][CH3:23])=[CH:15]4)=[N:9][N:10]=2)[CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([F:42])[CH:41]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO.C(Cl)Cl>[F:35][C:36]1[CH:37]=[C:38]([C:2]2[CH:3]=[C:4]([F:26])[C:5]3[N:6]([C:8]([C:11]([F:24])([F:25])[C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][C:16]([O:22][CH3:23])=[CH:15]5)=[N:9][N:10]=3)[CH:7]=2)[CH:39]=[C:40]([F:42])[CH:41]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COc1cnc2ccc(C(F)(F)c3nnc4c(F)cc(Cl)cn34)cc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CO
Solvent: ClCCl
Product: COc1cnc2ccc(C(F)(F)c3nnc4c(F)cc(-c5cc(F)cc(F)c5)cn34)cc2c1
Temperature: 100 °C
Yield: 17.5 %

Procedure:
A sealable microwave vial was charged with 6-((6-chloro-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline (342.05 mg, 903 μmol), palladium(II) acetate (30 mg, 135 μmol), potassium phosphate (575 mg, 2709 μmol), 3,5-difluorophenylboronic acid (285 mg, 1806 μmol), and X-Phos (129 mg, 271 μmol). The tube was sealed, and flushed with N2. Dioxane (9 mL), then H2O (1 mL) were added and the mixture was sparged with N2 for 10 min, then heated at 100° C. for 24 h. The mixture was cooled to rt and concentrated absorbed onto a 5 g loading cartridge for MPLC purification using a 98:2 CH2Cl2: MeOH to 90:10 CH2Cl2:MeOH gradient to give 6-((6-(3,5-difluorophenyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)-3-methoxyquinoline (72 mg, 17% yield). LRMS (ESI) m/z calcd for C23H14F5N4O (M+H) 457.1. found 457.0.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][N:7]([S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[CH:38][CH:37]=[CH:36]2)(=[O:30])=[O:29])[C:8]1[CH:27]=[CH:26][C:11]2[N:12]([CH3:25])[C:13]([CH2:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[NH:21])=[CH:18][CH:17]=3)=[N:14][C:10]=2[CH:9]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH3:51][O:52][C:53](Cl)=[O:54]>O>[CH3:2][O:3][C:4]([CH2:6][N:7]([S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:40]=1[N:39]=[CH:38][CH:37]=[CH:36]2)(=[O:29])=[O:30])[C:8]1[CH:27]=[CH:26][C:11]2[N:12]([CH3:25])[C:13]([CH2:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[N:21][C:53]([O:52][CH3:51])=[O:54])=[CH:18][CH:17]=3)=[N:14][C:10]=2[CH:9]=1)=[O:5]
Reactant: COC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OC)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.7 g (1.2 mmol) of 4-[(5-(N-methoxycarbonylmethyl-quinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-benzamidine-hydrochloride and 0.66 g (4.8 mmol) of potassium carbonate are dissolved in 5 ml water and 20 ml acetone and after the addition of 0.12 9 (1.3 mmol) of methylchloroformate the mixture is stirred for 30 minutes at ambient temperature. The solvent is evaporated off, the residue chromatographed on silica gel and eluted with methylene chloride/methanol 40:1. The desired fractions are concentrated by evaporation, the residue is triturated with ether and suction filtered.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1(O)[CH2:18][CH2:17]C[CH2:15][CH2:14]1.C1(N)CCCCC1.C(OC(C)C)(C)C>[Zn]>[C:1]1([CH2:7][CH2:8][C:9]([O:11][CH:12]2[CH2:17][CH2:18][CH2:13][CH2:14][CH2:15]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccccc1
Reactant: OC1CCCCC1
Agent: [Zn]
Solvent: CC(C)OC(C)C
Solvent: NC1CCCCC1
Product: O=C(CCc1ccccc1)OC1CCCCC1

Procedure:
Under a nitrogen atmosphere, a mixture of methyl 3-phenylpropionate (3.0 mmol), cyclohexanol (3.6 mmol), cyclohexylamine (3.6 mmol), the zinc cluster obtained in the above-described Example 1 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, an ester product, cyclohexyl 3-phenylpropionate, was obtained quantitatively. No formation of an amide product was observed.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:25]([CH3:28])([CH3:27])[CH3:26])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17]C(=O)OC(C)(C)C)[CH3:16])[N:8]=1.Cl.C(N(C(C)C)CC)(C)C.[CH3:39][O:40][CH2:41][C:42](Cl)=[O:43]>CO.C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([C:25]([CH3:27])([CH3:28])[CH3:26])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:42](=[O:43])[CH2:41][O:40][CH3:39])[CH3:16])[N:8]=1
Reactant: C[C@@H](CNc1nccc(-c2[nH]c(C(C)(C)C)nc2Br)n1)NC(=O)OC(C)(C)C
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C(C)(C)C)nc2Br)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A solution of (S)-tert-butyl 1-(4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate (2.6 g, 4.4 mmol) in methanol was treated with aqueous 12 N HCl (1.4 mL. 16.8 mmol). The reaction was heated at 60° C. for 1 h, and allowed to cool to rt. The reaction was then concentrated and dried in vacuo to give 1.6 g of a crude residue which was carried forward without further purification. The residue was treated with diisopropylethyl amine (4.6 mL, 26.3 mmol) in dry DCM (18 mL), followed by the dropwise addition of methoxyacetyl chloride (0.44 mL, 4.8 mmol). The reaction mixture was stirred at rt for 1 h, then concentrated, in vacuo, to dryness. The remaining residue was dissolved in EtOAc (40 mL) was washed with water (2×), dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography (SiO2, 90:10-50:50 hexanes-EtOAc) to afford 1.3 g of (S)—N-(1-(4-(4-bromo-2-tert-butyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-yl)-2-methoxyacetamide:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]([O:24][CH2:25][CH3:26])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.O>CO.C(Cl)Cl>[CH2:25]([O:24][C:19]1[C:18]([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:26]
Reactant: CCOC(=O)C1(NC(=O)c2cccnc2OCC)Cc2ccccc2C1
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CCOc1ncccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 312 h
Yield: 140.4 %

Procedure:
A 100 mL flask containing 2-[(2-ethoxy-pyridine-3-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester ([313], 340 mg, 0.96 mmol) is charged with 1,4-dioxane (4 mL) and MeOH (4 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2 mL) is added followed by the LiOH monohydrate (102 mg, 2.42 mmol). After 13 days, tlc analysis (silica, 10% MeOH/DCM) indicates that the starting material is completely consumed. The contents of the flask are diluted with iPrOH (30 mL). Dowex Highly Acidic Ion Exchange Resin (2 g) is added. The reaction flask is capped and allowed to stir at ambient temperature. After 18 h, additional iPrOH (35 mL) is added to the reaction flask. The contents of the reaction flask are filtered through a pad of Celite and concentrated under reduced pressure by pumping to constant weight to yield 0.44 g of white solid. This material is dissolved in a mixture of DCM (10 mL) and iPrOH (3 mL). Celite (15 g) is added to the flask. The solvent is removed under reduced pressure. The remaining material is transferred to a 40 mL plastic syringe that is fitted with a fritted disk. The syringe is fitted onto an ISCO Companion which had a 40 g column (silica). The following gradient is applied. 1% IPrOH/DCM for 4 column volumes. Then a linear gradient to 50% iPrOH/DCM over 10 column volumes. Hold at 50% iPrOH/DCM for 2 Column Volumes. 14 mL fractions are collected. Fractions 39-41 are combined and evaporated by pumping to constant weight to yield white solid (0.28 g, 89%).
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([O-])[CH:4]=[C:3]([CH2:8][C:9]#[N:10])[CH:2]=1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:4]1[C:3]([CH2:8][C:9]#[N:10])=[CH:2][CH:1]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#CCc1ccc[n+]([O-])c1
Product: N#CCc1cccnc1Cl
Temperature: 6 °C

Procedure:
(1-Oxypyridin-3-yl)acetonitrile (I115) (4.00 g, 29.8 mmol) was added slowly to a stirred solution of POCl3 (50 mL). The mixture was heated to 80° C. in 5-7° C. increments every 10-15 minutes. The reaction was then heated at reflux for 3 hours. Excess POCl3 was removed by distillation and the brown residue carefully poured on to cold water (200 mL). A saturated solution NaHCO3 (300 mL) was then added carefully. Solid NaHCO3 was added in portions to the aqueous mixture until the evolution of gas ceased. The aqueous layer was separated in to two portions (250 mL each) and each portion was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (200 mL) and dried over Na2SO4. The solvent was removed and the residue purified by column chromatography on silica gel (0-100% EtOAc in petroleum benzine) to afford a mixture of two isomeric compounds. The mixture was re-purified by column chromatography on silica gel (0-40% diethyl ether in petroleum benzine 40-60° C.) to afford the title compound (I116) (0.932 g, 20%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J=4.8, 1.8 Hz, 1H), 7.90 (ddt, J=7.6, 1.7, 0.7 Hz, 1H), 7.34 (dd, J=7.6, 4.8 Hz, 1H), 3.87 (s, 2H). LCMS Method C: rt 4.50 min; m/z 153 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:18]([C:19]([NH:21][CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[N:25]=2)[CH3:23])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:32])[N:10]1[C@H:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[NH:39][S:40]([CH3:43])(=[O:42])=[O:41].C(N(CC)CC)C.[C:51](OC(=O)C)(=[O:53])[CH3:52]>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[C:51]([O:31][CH2:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:22]([NH:21][C:19]([C@@H:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:32])[N:10]([C@H:33]3[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]3[NH:39][S:40]([CH3:43])(=[O:41])=[O:42])[C@H:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[O:20])[CH3:23])[N:25]=1)(=[O:53])[CH3:52]
Reactant: CC(NC(=O)[C@@H]1c2ccccc2C(=O)N([C@H]2CCCC[C@@H]2NS(C)(=O)=O)[C@H]1c1ccc(Cl)cc1Cl)c1cccc(CO)n1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1cccc(C(C)NC(=O)[C@@H]2c3ccccc3C(=O)N([C@H]3CCCC[C@@H]3NS(C)(=O)=O)[C@H]2c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 714 mg of (3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)pyridin-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 14.3 ml of chloroform was cooled to 0° C., and 0.23 ml of triethylamine, 0.16 ml of acetic anhydride, and 6.8 mg of DMAP were added thereto in this order, followed by stirring at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate-water was added thereto for liquid separation, followed by washing with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain {6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}methyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=3[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:29]#[N:30]>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:22]2[C:17](=[CH:18][C:19]3[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=3[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:29]#[N:30]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: COc1ccc2cc3c(Cl)c(C#N)cnc3cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cc3c(Nc4ccc(Cl)cc4Cl)c(C#N)cnc3cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
According to the procedure of Example 14, a reaction mixture of 487.7 mg (3.01 mmol) of 2,4-dichloroaniline and 120.6 mg (3.01 mmol) of sodium hydride in 15 mL of anhydrous DMF is stirred at room temperature for 0.5 hour. To the mixture is added 367.0 mg (1.37 mmol) of 4-chloro-8-methoxybenzo[g]quinoline-3-carbonitrile. The resulting mixture is heated at 55° C. for 0.5 hour. After work up, 443.3 mg (82.1%) of 4-(2,4-dichloroanilino)-8-methoxybenzo[g]quinoline-3-carbonitrile is obtained as a yellow solid, mp>260° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.Br[CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=[O:33].C(N(CC)CC)C>C(#N)C>[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][N:24]([CH2:28][C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[CH:32]=[O:33])[CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1
Reactant: O=Cc1cccc(CBr)c1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C=O)c4)CC3)C2)cs1

Procedure:
A solution of (2-methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.408 g), 3-(bromomethyl)benzaldehyde (0.205 g) and triethylamine (0.36 mL) in acetonitrile (10 mL) was stirred at room temperature overnight. The solution was concentrated in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed twice with water, once with brine, then dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 5% methanol in dichloromethane to afford the subtitled compound as a yellow gum. Yield 0.325 g.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])[CH2:2][C:3]#[CH:4].[N:16]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[N+:17]=[N-:18].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].N>[O-]S([O-])(=O)=O.[Cu+2].O.C(O)(C)(C)C>[O:15]=[C:6]1[C:7]2[C:8](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:10])[N:5]1[CH2:1][CH2:2][C:3]1[N:18]=[N:17][N:16]([CH2:19][O:20][C:21](=[O:26])[C:22]([CH3:24])([CH3:23])[CH3:25])[CH:4]=1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Agent: [Cu+2]
Agent: N
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)C(=O)OCn1cc(CCN2C(=O)c3ccccc3C2=O)nn1
Reaction time: 4 h
Yield: 88.7 %

Procedure:
702 mg (3.52 mmol) of N-(3-butynyl)phthalimide and 552 mg (3.51 mmol) of 2,2-dimethylpropionic acid azidomethyl ester are suspended in a water/t-butanol mixture (1/1, 10.5 ml). 0.18 ml of a 1M CuSO4 solution is added. 206 mg (1.04 mmol) of sodium ascorbate are then added. After 4 hours, the reaction is stopped by adding aqueous ammonia solution, and the reaction medium is extracted with EtOAc. The organic phase is then washed with brine and dried over MgSO4, filtered and concentrated. 1.11 g of 2,2-dimethylpropionic acid 4-[2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]-[1,2,3]triazol-1-ylmethyl ester in the form of a yellow oil are obtained in a yield of 88%.
Reaction SMILES: [H-].[Na+].O[C:4]1[C:13](O)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][NH:8][C:9]2=[S:15].[CH3:16]I>CCCCCC.C1COCC1.CCOCC>[CH3:16][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][NH:8][C:9]2=[S:15]
Reactant: CI
Reactant: Oc1ccc2c(c1O)CCNC2=S
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc2c1CCNC2=S
Reaction time: 0.5 h

Procedure:
To 0.15 g of 60% sodium hydride (3.70 mmol) which was washed with n-hexane and suspended in 15 ml of THF was added dropwise at 0 a solution of 0.50 g (2.82 mmol) of 3,4-dihydro-5,6-dihydroxy-1(2H)-isoquinolinethione in 5 ml of THF. The thick white suspension which formed was stirred for 0.5 hours at 0°-5° and then 0.45 g (2.82 mmol) of methyl iodide in 5 ml THF was added and stirring continued for one hour. The resulting yellow solution was diluted with ether, washed with saturated NaCl, dried (Na2SO4), and concentrated. The resulting oil was recrystallized from 1 ml of n-hexane to give pale yellow crystals, 0.55 g (100%); mp 43°-45°.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH3:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].Cl>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([OH:23])=[O:22])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH3:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CSc1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: Cl
Agent: [Na+]
Product: CSc1ncn2cc(C3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12

Procedure:
(1S,5R,6S)-6-((1R)-1-Hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylic acid was prepared from sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate and a 1.0 N aqueous hydrochloric acid solution. The title compound (33.5 mg) was obtained using this compound (103.0 mg), 123.7 mg of benzyltriethylammonium chloride, 113.3 mg of 1-(2ethyl-1-butyloxycarbonyloxy)ethyl chloride, 54.9 mg of triethylamine, and 24 ml of DMF according to the method described in Publication No. 504039/1999 of the Translation of International Patent Application.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[Cl:28][C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[Cl:28][C:29]1[C:30]([NH2:44])=[N:31][CH:32]=[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:19])=[O:20])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)[CH:34]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)c(Cl)c2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)c(Cl)c4)nc3s2)CC1
Yield: 89.8 %

Procedure:
4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine (0.8 g, 1.7 mmol) was reacted with 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.6 g) according to General Procedure Suzuki to provide 376 (0.8 g) following silica gel purification (0-15% MeOH in CH2Cl2) MS (Q1) 524 (M)+.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[OH:7][C:8]1[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[C:11]([CH3:18])([CH3:17])[C:10](=[O:19])[C:9]=1[C:20]([C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1)=O.ClC1C(C)(C)C(=O)C(C)(C)C(=O)C=1C(C1C(C)=NC(C(F)(F)F)=CC=1)=O.C(OCC)(=O)C>ClCCl.CN(C)C=O.CCCCCC>[Cl:4][C:20]([C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1)=[C:9]1[C:8](=[O:7])[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[C:11]([CH3:18])([CH3:17])[C:10]1=[O:19]
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)C(C)(C)C(=O)C(C)(C)C1=O
Reactant: O=C(Cl)C(=O)Cl
Agent: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(Cl)C(C)(C)C(=O)C(C)(C)C1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1C(Cl)=C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O
Reaction time: 0.5 h

Procedure:
7.0 g (55 mmol) of oxalyl chloride are introduced into 18.5 g (50 mmol) of 5-hydroxy-2,2,6,6-tetramethyl-4-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)cyclohex-4-ene-1,3-dione (compound A2-B354), dissolved in 50 ml of dichloromethane; 5 drops of dimethylformamide are added, and the mixture is slowly heated up to boiling point. After approximately 30 minutes, after the evolution of gas has ceased, the mixture is evaporated and the product is crystallized by adding n-hexane. The main product obtained is pure 5-chloro-2,2,6,6-tetramethyl-4-(2-methyl-6-trifluoromethylpyridine3-carbonyl)cyclohex-4-ene-1,3dione, m.p. 119.5-120° C. Further HPLC-separation of the mother liquor using 5-10% ethyl acetate in hexane gives the isomer 6-[chloro-(2-methyl-6-trifluoromethylpyridine-3-yl)methylene]-2,2,4,4-tetramethylcyclohexane-1,3,5-trione, m.p. 92.5-93° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:17][C:18](=[O:33])[C:19]1[CH:24]=[CH:23][C:22]([C:25]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[C:21]([CH3:32])[CH:20]=1)[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[N:8]=1.C(N(C(C)C)CC)(C)C.[O:43]=[C:44]1[NH:48][CH2:47][CH:46]([C:49](O)=[O:50])[CH2:45]1>CS(C)=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C@@H:6]([NH:17][C:18](=[O:33])[C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)=[O:26])=[C:21]([CH3:32])[CH:20]=3)[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:49]([CH:46]3[CH2:45][C:44](=[O:43])[NH:48][CH2:47]3)=[O:50])=[N:8][C:9]=2[CH:15]=1
Reactant: O=C1CC(C(=O)O)CN1
Reactant: Cc1cc(C(=O)N[C@@H](CCCCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](CCCCNC(=O)C2CNC(=O)C2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1d from N-[(1S)-5-amino-1-(5-chloro-1H-benzimidazol-2-yl)pentyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, PFTU, diisopropylethylamine, and 5-oxopyrrolidine-3-carboxylic acid in dimethylsulfoxide. HPLC-MS results: retention time: 2.04 minutes; C30H35ClN6O4 (579.10); mass spectrum: (M−H)−=578.