Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([NH:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])=[O:19])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[O:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[C:15]([I:16])=[C:6]([C:7]([NH:9][CH:10]([CH2:13][OH:14])[CH2:11][OH:12])=[O:8])[C:5]([I:17])=[C:4]([C:3]=1[I:26])[C:18]([NH:20][CH:21]([CH2:24][OH:25])[CH2:22][OH:23])=[O:19])(=[O:40])[CH3:39]
Reactant: Nc1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)Nc1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
5-Amino-N,N'-bis(1,3-dihydroxy-2-propyl)-2,4,6-triiodoisophthalamide (300 g) was suspended in acetic anhydride (1.5 1) at 90° (in an oil bath) and then p-toluenesulphonic acid (3 g) was added. The mixture was heated for 41/2 hours and then cooled slowly to room temperature. The product was collected on a filter and washed with small amounts of acetic anhydride. Yield: 353 g. The product was suspended in a mixture of methanol (600 ml) and water (300 ml) at room temperature and the pH was adjusted to about 11.5 by adding 5N sodium hydroxide (200 ml). This mixture was heated at 50° C. and more 5 N sodium hydroxide (235 ml) was added dropwise in such a manner that the pH was kept at about 10.5. After 2-3 hours the pH did not decrease, and the hydrolysis was completed. After cooling to room temperature the mixture was acidified with 6 N hydrochloric acid to about pH 6. After stirring for two hours at room temperature, the mixture was cooled to 3° for 2-3 days. The product was collected on a filter, suspended in water (500 ml) and filtered again. Yield: 257 g. Melting point: above 270°. (Found: C 25.68; H 2.85; I 51.0; N 6.03. Calc. for C16H20I3N3O7 : C 25.72;H 2.70; I 50.96; N 5.62) TLC (precoated TLC Plates Silica Gel 60 F-254 from Merck A.G. and developed in CHCl3 : MeOH=70:30) showed one spot with Rf value 0.38.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C)=[O:29])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[Li+].Cl>CO.O>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[CH:25][CH:26]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3nc(C(C)C)no3)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)cc3)CC2)n1
Yield: 97.1 %

Procedure:
Methyl 2-(4-(2-((1S,2R)-2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)cyclopropyl)ethoxy)phenyl)acetate (0.55 g, 1.28 mmol) was dissolved in MeOH (5 ml) and lithium hydroxide (154 mg, 6.43 mmol) in 2 mL of water was added. The mixture was stirred at RT for 1 h and neutralized to pH 6 with 5 N HCl, extracted with EtOAc (50 ml). The EtOAc phase was dried over MgSO4, and evaporated to afford 514 mg (97%) of the desired product. LC/MS (m/z): 414 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)[CH:20]=1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Reactant: OB(O)c1cccnc1
Product: CN(C(=O)Oc1ccc(-c2cccnc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and pyridine-3-boronic acid. The crude product was purified by preparative HPLC (Gilson) (5%, brown oil).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([CH3:12])=[CH:7]2.[C:14](OCC)(OCC)(OCC)[CH3:15]>>[CH3:14][C:15]1[O:13][C:3]2[CH:4]=[CH:5][C:6]3[CH:7]=[C:8]([CH3:12])[CH:9]=[N:10][C:11]=3[C:2]=2[N:1]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1cnc2c(N)c(O)ccc2c1
Product: Cc1cnc2c(ccc3oc(C)nc32)c1
Temperature: 25 °C

Procedure:
3.48 g (20 mmol) of 8-amino-7-hydroxy-3-methylquinoline and 16.2 g (100 mmol) of triethyl orthoacetate are heated at 100° C. for 1 hour. The reaction mixture is then allowed to cool to room temperature, 50 ml of petroleum ether are added while stirring vigorously, and the precipitate is filtered off with suction.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[N+:6]([C:9]1[C:10](O)=[C:11]2[S:17][CH:16]=[CH:15][C:12]2=[N:13][CH:14]=1)([O-:8])=[O:7]>>[Cl:3][C:10]1[C:9]([N+:6]([O-:8])=[O:7])=[CH:14][N:13]=[C:12]2[CH:15]=[CH:16][S:17][C:11]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccsc2c1O
Product: O=[N+]([O-])c1cnc2ccsc2c1Cl
Temperature: 110 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
POCl3 (20.0 mL) was added to 6-nitrothieno[3,2-b]pyridin-7-ol (1.56 g, 7.95 mmol). The mixture was stirred at 110° C. for 3 h. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in DCM (150 mL), and a saturated aq. NaHCO3 (150 mL) was added slowly. The organic layer was washed with water (100 mL) and brine (100 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (0 to 30% EtOAc in hexanes) to afford the sub-title compound as a pale yellow solid (1.39 g, 82%). LCMS calc. for C2H4ClN2O2S (M+H)+: m/z=215.0. found 215.0.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])[CH:10]=[CH:9][C:8]=2[NH2:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:26]([C:28]1[N:29]=[C:30]([C:41]([O-])=[O:42])[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=1)#[N:27].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:16])=[O:17])[CH:10]=[CH:9][C:8]=2[NH:24][C:41]([C:30]2[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[C:28]([C:26]#[N:27])[N:29]=2)=[O:42])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.7 %

Procedure:
A solution of 132 mg (0.377 mmol) of 2-cyclohex-1-enyl-4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (as prepared in the previous step) in CH2Cl2 (15 mL) was treated with 126 mg (0.414 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 93.9 mg (0.565 mmol) of PyBroP to form a slurry, which was treated with 197 μL (1.13 mmol) of DIEA. The mixture was stirred at RT for 3.5 h, diluted with CH2Cl2 (15 mL), and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 221 mg (98%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C29H41N5O5SSi, 600.3 (M+H). found 599.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:39])([F:38])[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35](O)=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCN(CC)CC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:35]([C:30]3[C:29]([C:26]4[CH:27]=[CH:28][C:23]([C:22]([F:21])([F:38])[F:39])=[CH:24][CH:25]=4)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:36])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
To a stirred solution of 4-(4-aminophenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.18 g), 4′-trifluoromethyl-biphenyl-2-carboxylic acid (0.17 g), HOBt (0.1 g), and Et3N (80 mg) in CH2Cl2 (10 mL) was added at room temperature EDCl (0.15 g) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3 and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with petroleum ether/AcOEt (70/30) to give the title compound (0.25 g) as an orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.Cl>CS(C)=O.O>[N:26]1[CH:27]=[CH:28][C:23]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)=[CH:24][CH:25]=1
Reactant: Clc1ccncc1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cccc2cc(Oc3ccncc3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-hydroxy-1-napthoic acid (2 g, 10.6 mmol) in DMSO (5 mL), Cs2CO3 (14 g, 42.4 mmol) was added and stirred at RT 10 min. 4-Chloropyridine hydrochloride (1.9 g, 12.7 mmol) was added in one portion and the reaction mixture heated to 140° C. for 12 h. The reaction mixture was cooled to RT, diluted with water and made pH 5 using 6 N HCl, at which point a brown precipitate crashed out. The solid was filtered and rinsed with water and hexanes to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=2[C:12]([OH:14])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N:37]1[CH:42]=[C:41]([C:43]2[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=2)[NH2:46])[CH:40]=[N:39][CH:38]=1>ClCCl>[N:37]1[CH:42]=[C:41]([C:43]2[CH:44]=[C:45]([NH:46][C:12]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[NH:3][C:2]([CH3:1])=[C:10]4[CH3:11])=[O:14])[CH:47]=[CH:48][CH:49]=2)[CH:40]=[N:39][CH:38]=1
Reactant: Nc1cccc(-c2cncnc2)c1
Reactant: Cc1[nH]c2c(C(=O)O)cccc2c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1[nH]c2c(C(=O)Nc3cccc(-c4cncnc4)c3)cccc2c1C
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
To a suspension of 2,3-dimethylindole-7-carboxylic acid (95 mg) and 1-hydroxybenzotriazole (81 mg) in dichloromethane (3 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg), and the mixture was stirred for 5 minutes. After adding 3-(pyrimidin-5-yl)aniline (94 mg) and 4-dimethylinopyridine (92 mg), the mixture was stirred for 24 hours. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 3% methanol in dichloromethane to give N-(3-(pyrimidin-5-yl)-phenyl)-2,3-dimethyl-1H-indole-7-carboxamide (117 mg, 68.4%).
Reaction SMILES: CCCCCC.[H-].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.[CH:19]([N:22]=[C:23]=[S:24])([CH3:21])[CH3:20]>C1COCC1>[CH:19]([NH:22][C:23]([N:15]1[C:16]2[C:12](=[CH:11][C:10]([Cl:9])=[CH:18][CH:17]=2)[CH:13]=[CH:14]1)=[S:24])([CH3:21])[CH3:20]
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CC(C)N=C=S
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)NC(=S)n1ccc2cc(Cl)ccc21
Reaction time: 1 h
Yield: 61.7 %

Procedure:
A stirred slurry of hexane washed potassium hydride (0.87 g, 21.8 mmol) in 50 mL of dry THF was treated portionwise with 5-chloroindole (3.3 g, 21.8 mmol). The mixture was heated at reflux until a clear solution was obtained. A solution of isopropyl isothiocyanate (2.2 g, 21.8 mmol) in 5 mL THF was slowly added and stirring was continued for 1 hour. The solvent was evaporated and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The amber solids were recrystallized from EtOH to provide 3.4 g of the title compound as a tan solid, m.p. 135° C. (62% of theory).
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:5]=1[CH:6]=[O:7].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20]>O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][C:4]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1cc(Cl)ccc1Cl
Reactant: Fc1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1cc(Cl)ccc1Sc1ccccc1F

Procedure:
solution of 3.4 g sodium hydroxide in 6 ml of water and then 14 g of 2,5-dichlorobenzaldehyde (H. Erdmann, Justus Liebigs Ann. Chem. 272, 155, 1893) are added to a solution of 10.8 g 2-fluorothiophenol (reference above) in 20 ml of hexamethylphosphortriamide. Then, the mixture is heated for 5.5 hours to 100° C. After cooling it is diluted with 150 ml of water and extracted with benzene. The extract is washed with a 5% sodium hydroxide solution and with water, dried with magnesium sulfate and evaporated. Crude 2-(2-fluorophenylthio) 5-chlorobenzaldehyde is obtained which is then recrystallized from 20 ml ethanol; 16.0 g, m.p. 85.5°-88° C. A further crystallization affords an analytically pure product, m.p. 87°-88° C.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH:26]=1)[CH2:17][CH:18]([C:23](=O)[CH3:24])[C:19](OC)=[O:20])#[N:10]>CO>[NH2:7][C:6]1[N:8]=[C:19]([OH:20])[C:18]([CH2:17][C:16]2[CH:26]=[C:12]([CH2:11][C:9]#[N:10])[CH:13]=[CH:14][C:15]=2[O:27][CH3:28])=[C:23]([CH3:24])[N:5]=1
Reactant: COC(=O)C(Cc1cc(CC#N)ccc1OC)C(C)=O
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CO
Product: COc1ccc(CC#N)cc1Cc1c(C)nc(N)nc1O
Temperature: 50 °C

Procedure:
Guanidine carbonate (5 g) was added to a stirred solution of the product from step (i) (5.01 g) in MeOH (80 mL). The suspension was heated at 50° C. for 15 h and then the solvent evaporated under reduced pressure. The residue was diluted with water (20 mL) and diethyl ether (20 mL). The resulting precipitate was collected by filtration and the solid was dried under vacuum to give the subtitle compound as an orange solid, 2.8 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[O:12]1[CH2:16][CH2:15][C:14]2[CH:17]=[C:18](C=O)[CH:19]=[CH:20][C:13]1=2>>[O:12]1[CH2:16][CH2:15][C:14]2[CH:17]=[C:18]([NH:1][C:2]3[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=3[CH3:7])[CH:19]=[CH:20][C:13]1=2
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: COC(=S)c1cc(N)c(C)s1
Product: COC(=S)c1cc(Nc2ccc3c(c2)CCO3)c(C)s1

Procedure:
Using the procedure described in Example 220, step (a), 60 mg (0.29 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 42.9 mg (0.29 mmol) of 2,3-dihydrobenzo[b]furan-5-carboxaldehyde, and 135 mg (2.2 equiv, 0.63 mmol) of NaHB(OAc)3 were allowed to react to give methyl 4-(2,3-dihydrobenzo[b]furan-5-ylamino)-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C16H17NO3S2, 336.07 (M+H), found 334.3 (imine), 335.3.
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].C([Sn](CCCC)(CCCC)[C:32]1[S:36][C:35]2=[C:37]([S:40][C:41]([F:44])([F:43])[F:42])[N:38]=[CH:39][N:34]2[CH:33]=1)CCC>>[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:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([C:32]3[S:36][C:35]4=[C:37]([S:40][C:41]([F:44])([F:43])[F:42])[N:38]=[CH:39][N:34]4[CH:33]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SC(F)(F)F)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(SC(F)(F)F)c4s3)[C@H](C)[C@H]12
Yield: 14.8 %

Procedure:
The procedure of Example 1a) was repeated, except that 743 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.06 g 2-(tri-n-butylstannyl)-7-trifluoromethylthioimidazo[5,1-b]thiazole were used as the starting compounds. Thus, 172 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-trifluoromethylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[CH2:8]=[O:9]>CCOCC>[OH:9][CH2:8][CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: C=O
Reactant: Cc1ccncn1
Solvent: CCOCC
Product: OCCc1ccncn1

Procedure:
A mixture of 4-methylpyrimidine (10 g, 106 mmol) and para-formaldehyde (3 g) was stirred in a 50 mL sealed capacity pressure vessel at 165° C. for 3.5 hours. After cooling, ether was added and the solvents evaporated to afford an oil. This was purified by silica column chromatography using a Flashmaster system, eluting with dichloromethane, then chloroform, ether, and finally ethyl acetate. The ethyl acetate fractions were evaporated to afford the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[N:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:21]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1CN1CCOCC1)OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COc1ccc2c(c1CN1CCOCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 12.2 %

Procedure:
A solution of 6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.131 g, 0.500 mmol) in methanol (2 mL) was added with 1H-indazole-3-carboxaldehyde (0.0877 g, 0.600 mmol) and piperidine (0.00425 g, 0.0500 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/methanol), and the resulting crude product was crystallized from ethyl acetate. The precipitated solid was collected by filtration, and then suspended in acetonitrile and thereby washed to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.0238 g). Further, the filtrate was concentrated, and the resulting residue was purified again by silica gel column chromatography (chloroform/methanol) to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.0254 g) (0.0492 g, 25% in total).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.C(N[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)C>>[CH2:34]([NH:33][S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])[C:35]1[CH:30]=[CH:31][CH:32]=[CH:37][CH:36]=1
Reactant: CCNCCc1ccccn1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)NCc1ccccc1)CC2

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and ethyl-(2-pyridin-2-yl-ethyl)-amine. MS (ESI): 484.4 (MH+).
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][N:9]([NH2:12])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:30]3[N:31]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=4[Cl:44])[N:32]=[C:33]([C:34](Cl)=[O:35])[C:29]=3[S:28][CH2:27][C:25]=2[CH:26]=1>C(Cl)Cl>[CH2:2]1[C:6]2([CH2:11][CH2:10][N:9]([NH:12][C:34]([C:33]3[C:29]4[S:28][CH2:27][C:25]5[CH:26]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=5[C:30]=4[N:31]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][C:38]=4[Cl:44])[N:32]=3)=[O:35])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)c1nn(-c2ccc(Cl)cc2Cl)c2c1SCc1cc(Cl)ccc1-2
Reactant: NN1CCC2(CCCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CCC2(CCCC2)CC1)c1nn(-c2ccc(Cl)cc2Cl)c2c1SCc1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
A solution of 0.28 g of 8-azaspiro[4.5]dec-8-ylamine hydrochloride and 0.41 ml of triethylamine in 15 ml of DCM is cooled to 0° C., 0.6 g of the acid chloride prepared in Example 1, step A, in 10 ml of DCM is added dropwise and the mixture is left for 4 hours, with stirring, at RT. The mixture is extracted with DCM, the organic phase is washed with water, with a saturated NaCl solution, dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with the toluene/AcOEt (95/5; v/v) mixture. 0.45 g of the expected compound is obtained in amorphous form.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([O:27]CC)=[O:26])[C:17]2=[O:33])=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[C:17]2=[O:33])=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N2CCN(Cc3cccc(C(=O)O)c3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 97 %

Procedure:
To a solution of ethyl 3-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate (0.093 g, 0.19 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL) was added lithium hydroxide monohydrate (0.032 g, 0.77 mmol) at ambient temperature. The resulting reaction mixture was heated to reflux for 14 hours. The solvent was removed in vacuo, and the residue was neutralized to pH 3-4 with 10% hydrochloric acid solution. The resulting precipitate was filtered, washed with water (30 mL), hexane (30 mL) and dried to afford the title compound as a colorless solid in 97% yield (0.083 g): mp 120-123° C. (water); 1H NMR (300 MHz, DMSO-d6) δ 13.10 (br s, 1H), 8.49 (t, J=6.0 Hz, 1H), 7.91-7.88 (m, 2H), 7.40-7.38 (m, 2H), 7.32-7.16 (m, 5H), 4.48 (s, 2H), 4.35-4.33 (m, 2H), 4.01-3.96 (m, 2H), 3.48-3.42 (m, 2H), 2.44 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.5, 162.2, 157.8, 155.6, 151.3, 142.0, 140.1, 130.4, 130.1, 128.7, 128.2, 127.6, 127.1, 118.3, 47.1, 43.0, 42.4, 42.2, 17.5; MS (ES+) m/z 451.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([Cl:9])([Cl:8])[Cl:7].[C:13]([O-:16])(=[O:15])[CH3:14].[Cs+].C(O)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:13]([O:16][CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([Cl:9])([Cl:8])[Cl:7])(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: COC(=CC(=O)C(Cl)(Cl)Cl)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=CC(=O)C(Cl)(Cl)Cl)COC(C)=O

Procedure:
29.6 g (0.1 mol) of 5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, 19.1 g of cesium acetate, 5 g of tetrabutylammonium bromide and 8 g of acetic acid were stirred in 300 ml of acetonitrile at 25° C. for 8 h. The precipitate was filtered off and the organic phase was concentrated under reduced pressure.