Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(N(Cl)[Cl:12])(=O)=O)=CC=1.Cl.[CH3:15][CH:16]([CH2:28][CH3:29])[CH2:17][O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>C(O)(=O)C>[CH3:15][CH:16]([CH2:28][CH3:29])[CH2:17][O:18][C:19](=[O:27])[C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[C:24]([Cl:12])[CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)N(Cl)Cl)cc1
Reactant: CCC(C)COC(=O)c1ccc(O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCC(C)COC(=O)c1ccc(O)c(Cl)c1
Reaction time: 8 h
Yield: 144.2 %

Procedure:
On the other hand, dichloramine T (28.0 g, 0.12 mol) was dissolved in acetic acid (450 ml), and hydrochloric acid (1.5 ml) was added. The resulting solution was dropwise added to a solution of the above p-hydroxybenzoic acid 2-methyl-butyl ester (50 g, 0.24 mol) dissolved in acetic acid (450 ml), followed by refluxing the mixture, allowing to stand overnight, distilling off acetic acid and filtering off deposited crystals to obtain 3-chloro-4-hydroxy-benzoic acid 2-methyl-butyl ester (42 g) (b.p. 135°~138° C./4 mmHg).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>ClCCl>[CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Br:14])=[CH:6][CH:5]=1
Reactant: CC(C)=Cc1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)=Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-(2-methylprop-1-en-1-yl)benzyl alcohol (0.60 g) and carbon tetrabromide (1.2 g) in dichloromethane (12 mL) was added triphenylphosphine (0.97 g) at 0° C., and the mixture was stirred at room temperature for 3.5 hours. To the reaction mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane) to give 4-(2-methylprop-1-en-1-yl)benzyl bromide. To a solution of methyl acetoacetate (0.44 mL) in tetrahydrofuran (17 mL) was added sodium hydride (60%, 0.18 g) at 0° C., and the mixture was stirred for 10 minutes. To the reaction mixture was added a solution of 4-(2-methylprop-1-en-1-yl)benzyl bromide in tetrahydrofuran (3 mL), and the mixture was heated under reflux for 3.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in toluene (8 mL). To the solution was added hydrazine monohydrate (0.54 mL), and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to 0° C., and the resulting precipitates were collected by filtration, washed with water and hexane, and dried under reduced pressure to give 5-methyl-4-{[4-(2-methylprop-1-en-1-yl)phenyl]methyl}-1,2-dihydro-3H-pyrazol-3-pyrazol-3-one (0.31 g).
Reaction SMILES: [SH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)#[N:14]>N1C=CC=CC=1>[CH3:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]2[S:1][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:14][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Cc1cc(C)c(S)c(C(=O)O)c1
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: Cc1cc(C)c2sc(-c3ccccn3)nc(=O)c2c1
Yield: 50.8 %

Procedure:
A mixture of 2-mercapto-3,5-dimethylbenzoic acid (1.6 g, 8.8 mmol), 2-cyanopyridine (1.0 g, 9.7 mmol) and pyridine (15 ml) was refluxed for 12 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (1.2 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@H:19]4[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][C@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(-c2cc3c4c(c2)[C@H]2CNCC[C@H]2N4CCC3)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Tert-butyl (±)-cis-2-(2,3-dichlorophenyl)-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (55 mg, 0.12 mmol) was dissolved in 20% TFA in methylene chloride (4 mL) and was stirred at RT for 2 h. The reaction was solution was cooled to 0° C. and basified with 1M NaOH until pH>14. The layers were separated. The aqueous phase was extracted the methylene chloride (2×10 ml). The organic layers were washed with brine and dried. Concentration afforded the title compound (43 mg, 100%) as a pale yellow amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.37 (dd, 1H, J=2.6, 7.3 Hz), 7.15-7.23 (m, 2 H), 6.97 (s, 1H), 6.92 (s, 1H), 3.43-3.46 (m, 1H), 3.31 (dt, 1H, J=4.4, 10.2), 3.03-3.11 (m, 2H), 2.81-2.94 (m, 2H), 2.60-2.80 (m, 4H), 2.11-2.20 (m, 2H), 1.89-1.98 (m, 1H), 1.74-1.85 (m, 1H) ppm. MS (CI, NH3): 359 (base, M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH2:28][OH:29])[CH:7]=2)[CH2:3][CH2:2]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]O.Cl>ClCCl.O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:28][O:29][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CN(C)CCO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CO)c2c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(COCCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of the product of step i) (130 mg) in dichloromethane (5 mL) was treated with (−/+)-10-camphorsulfonic acid (680 mg) and N,N-dimethylethanolamine (0.32 mL) and stirred at room temperature for 17 hours. 4N Hydrogen chloride in 1,4-dioxane (0.85 mL) was added and the reaction was stirred at room temperature for 6 hrs. Additional N,N-dimethylethanolamine (0.33 mL), (−/+)-10-camphorsulfonic acid (680 mg) and 4N hydrogen chloride in 1,4-dioxane (0.9 mL) were added and the reaction was stirred at room temperature for 60 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate (100 mL) solution. The organics were evaporated in vacuo, and the crude product was purified by HPLC to yield the title compound as a solid (25.0 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[N:2]1.Cl.[CH3:14][NH:15][O:16][CH3:17].N1C=CC=CC=1>O1CCCC1>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][N:2]=1)=[O:12]
Reactant: O=C(O)c1noc2ccccc12
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1noc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
1.0 g of benzo[d]isoxazole-3-carboxylic acid, 0.7 g of N,O-dimethylhydroxylamine hydrochloride, 2.3 g of 1-(3-dimethylaminopropyl-3-ethylcarbodiimide) hydrochloride and 1 ml of pyridine in 40 ml of tetrahydrofuran are placed in a round-bottomed flask. The mixture is stirred at ambient temperature for 20 h. The mixture is concentrated and the residue is taken up in 40 ml of ethyl acetate and 20 ml of water. The organic phase is washed with 20 ml of a 1N solution of sodium hydroxide and 20 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and then concentrated under reduced pressure. 1.1 g of compound are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(NC(=NC(C)C)O[C:19]([CH3:22])([CH3:21])[CH3:20])(C)C>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc2[nH]ccc2c1
Reaction time: 25 h
Yield: 59.3 %

Procedure:
Indole-5-carboxylic acid (1.00 g, 6.21 mmol) and tert-butyl N,N′-diisopropylcarbamimidate 2.29 g) were combined in 15 mL of THF and the reaction mixture was stirred for 25 hours. The reaction mixture was concentrated and the residue was purified on a silica gel column eluting with a gradient of 5% ethyl acetate/hexane to 100% ethyl acetate to provide tert-butyl 1H-indole-5-carboxylate (0.800 g, 3.68 mmol, 59%.)
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]=[O:29])[CH:9]=1.[CH2:40]1COCC1.C[Mg]Br.CCOCC>O>[CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([F:27])=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:28]([OH:29])[CH3:40])[CH:9]=1
Reactant: C1CCOC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C=O)nc2c(-c3cnc4ccc(F)cc4c3)cnn12
Agent: C[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CC(O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(-c3cnc4ccc(F)cc4c3)c2n1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde (11.0 g, 19.4 mmol) in anhydrous THF (200 mL, 2 mol) under nitrogen at 0° C. was added 3M methylmagnesium bromide in ether (9.69 mL, 29.0 mmol) dropwise. After 1 hour the reaction was complete by HPLC. Water (10 mL) was added over a 15 minute period to quench the reaction. Removed the flask from the ice bath and concentrated in vacuo. Dissolved the remaining residue in ethyl acetate, washed three times with water and then twice with brine. The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Purified the remaining crude material by flash chromatography (5-40% EtOAc/hex) to afford 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)ethanol (6.8 g; 60% yield) as a yellow solid. HPLC: 7.54 min (Method C). LCMS: ESI+ m/z of 584 (M+H)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[CH2:11](Br)[CH:12]=[CH2:13].C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[CH3:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH:12]=[CH2:11])=[CH:6][CH:5]=1)=[CH2:3]
Reactant: C=C(C)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc(C(=C)C)cc1
Yield: 63 %

Procedure:
A 10 g-portion of p-isopropenylphenol, 1.0 equivalent allyl bromide, 1.0 equivalent K2CO3, and 20 ml acetone were mixed and refluxed overnight. The reaction mixture was poured into 60 ml water and extracted with two portions of ether. The combined ether layers were washed with two portions of 10% aqueous NaOH, two portions of saturated aqueous NaCl and dried over K2CO3. Removal of solvent followed by distillation under reduced pressure gave a 63% yield of 1-(1-methylethenyl)-4-(2-propenyloxy)benzene, mp 22°-23° C.
Reaction SMILES: O.NN.[CH3:4][CH:5]([NH:11][C:12](=[O:25])[CH2:13][N:14]1C(=O)C2=CC=CC=C2C1=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(O)C>[NH2:14][CH2:13][C:12]([NH:11][CH:5]([CH3:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:25]
Reactant: CCCCCC(C)NC(=O)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCCCC(C)NC(=O)CN
Temperature: 25 °C

Procedure:
A solution of hydrazine hydrate (1.14 g; 22.8 mmol) and N-(1-methylhexyl)-2-phthalimidoacetamide (6.9 g; 22.8 mmol) in ethanol (50ml) was heated under reflux for 1 hour. It was then cooled to room temperature and evaporated in vacuo (Buchi, r.t.; then oil-pump, 0.5 mm/r.t./10 min.). The resultant semi-solid mixture was treated with dilutesulphuric acid (0.5 N; 85 ml) pre-cooled to 5°. The mixture was cooled to 0°, filtered and the precipitate mixed with more of the acid (2 N; 3×20 ml). The filtrate was kept in the refrigerator overnight and then filtered once more. After basification with sodium hydroxide solution (5 N; 40 ml), the mixture was extracted with dichloromethane (3×50 ml), the extracts dried (sodium sulphate) and evaporated in vacuo. The resultant oil was dried at 0.5 mm./r.t./0.5 h. T.l.c. (silica; chloroform:methanol: 3:2): 1 major spot, Rf. ca 0.5. I.v. and n.m.r. spectra were consistent with the structure. The product was purified as its hydrogen succinate.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][N:8]=1)[CH3:2].[N+:15]([CH2:18][CH3:19])([O-:17])=[O:16].C([O-])(=O)C.[NH4+]>C(O)(=O)C.O>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:18]([N+:15]([O-:17])=[O:16])[CH3:19])=[CH:9][N:8]=1)[CH3:2]
Reactant: CCOCCOc1ccc(C=O)cn1
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CCOCCOc1ccc(C=C(C)[N+](=O)[O-])cn1

Procedure:
A mixture of 8.3 g (42.6 mmol) of 2-(2-ethoxyethoxy)-pyridine-5-aldehyde, 5.53 g, (73.7 mmol) of nitroethane and 3.83 g (49.7 mmol) of ammonium acetate in 50 ml of glacial acetic acid is heated under reflux for 7 hours. The mixture is then diluted with water while cooling in ice, and the product is filtered off with suction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Oc1ccc(F)cc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1cc(Br)ccc1Oc1ccc(F)cc1
Yield: 98.3 %

Procedure:
In a manner similar to the method described in Example 50a, 5-bromo-2-fluorobenzaldehyde (4.1 g, 20 mmol) (Alfa) was reacted with 4-fluorophenol (2.5 g, 22 mmol)(Aldrich) and K2CO3 in N,N-dimethylacetamide to give 5-bromo-2-(4-fluoro-phenoxy)-benzaldehyde as a yellow solid (Yield 5.8 g, 97%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[N:5][CH:4]=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[H][H]>[Pd].C(O)C>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])=[N:5][CH:4]=[C:3]1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: [H][H]
Reactant: CCOC(=O)c1cnc(-c2ccccc2[N+](=O)[O-])[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2N)[nH]c1=O
Yield: 54.7 %

Procedure:
A mixture of ethyl 1,6-dihydro-6-oxo-2-(2-nitrophenyl)pyrimidine-5-carboxylate (0.91 g., 3.14 mmoles), 10% palladium on carbon (0.34 g.) and ethanol (200 ml.) was shaken in an atmosphere of hydrogen at an initial pressure of 3.5 kg./cm2. After hydrogen uptake ceased, the mixture was filtered and the filtrate concentrated. The residue was recrystallized from acetonitrile to give the title compound (0.445 g., 54.5%), m.p. 228°-230° (decomp.).
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[CH3:20][S:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:9]([OH:10])=[O:8])[CH2:12][CH2:13]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1CCC(C(=O)O)CC1
Yield: 73 %

Procedure:
1-Methanesulfonyl-piperidine-4-carboxylic acid benzyl ester (0.8 g, 26.7 mmol) from step 4, was dissolved in ethyl acetate (100 ml) and methanol (10 ml), Pd/C 10% (80 mg) was added and the resulting mixture was hydrogenated at 1 bar. The catalyst was filtered over celite, the solvent was removed under reduced pressure to give a white solid. Yield 73%, 0.4 g.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33]([O:35][C:36]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)=[O:37])[CH3:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:33]([O:35][C:36](=[O:37])[C:38]1[CH:39]=[CH:40][CH:41]=[C:42]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]2)=[O:24])[CH:43]=1)[CH3:34]
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-ethoxycarbonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (69%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16](=O)[NH:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=O)[CH2:14][N:13]([C:29](=[O:31])[CH3:30])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].C([O-])(=O)C.[NH4+:37]>>[CH3:1][O:2][C:3](=[O:32])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)[N:37]=2)[CH2:14][N:13]([C:29](=[O:31])[CH3:30])[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CN(C(C)=O)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
(1-{3-Acetyl-5-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-imidazolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (203 mg, 0.397 mmol) was dissolved in m-xylenes (4 mL) and heated at 135° C. Solid ammonium acetate (200 mg, 2.58 mmol) was added and the reaction was stirred at 135° C. After 120 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w 10% MeOH/hexanes) to yield the product {1-[1′-Acetyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (162 mg, 0.329 mmol): LCMS-ESI+: calc'd for C21H26BrN5O4: 492.4 (M+). Found: 492.3/494.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=1.O.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.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>[C:35]([CH2:34][CH2:33][C:21]1[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:4]2[CH:3]=[C:2]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=2)=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([OH:37])=[O:36]
Reactant: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)c1cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cccc(F)c2)c1
Temperature: 78 °C

Procedure:
To a solution of 4-[3-[7-(3-bromo-5-dimethylcarbamoyl-phenyl)-hept-6-ynyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (80 mg, 0.14 mmol) in EtOH (4 mL)/H2O (1 mL) were added 3-fluorophenylboronic acid (39 mg, 0.28 mmol), potassium carbonate (77 mg, 0.56 mmol) and Pd(PPh3)4 (3 mg, 0.0028 mmol). The mixture was heated at 78° C. for 5 h and then cooled to room temperature. The reaction mixture was filtered using a syringe filter 0.45 μm and the filtrate was concentrated under reduced pressure. The crude oil was then purified by preparative HPLC using acetonitrile/water gradient.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>N1C=CC=CC=1>[N+:17]([C:14]1[C:15]2[CH2:16][C@H:7]3[CH2:6][S:5][C:4](=[N:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[N:8]3[CH2:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: CSC1=[N+]2Cc3cccc([N+](=O)[O-])c3C[C@H]2CS1
Reactant: Nc1cccnc1
Agent: [I-]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc2c1C[C@H]1CSC(=Nc3cccnc3)N1C2
Reaction time: 6 h
Yield: 81.3 %

Procedure:
(S)-3-Methylthio-9-nitro-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (6 g.) is added to a solution of 3-aminopyridine (3 g.) in pyridine (100 cc.). After 6 hours at a temperature of about 20° C., the mixture is concentrated to dryness under reduced pressure (25 mm. Hg). The residue is dissolved in a mixture consisting of methylene chloride (300 cc.) and water (200 cc.). The organic phase is decanted, washed with water (3 × 200 cc.), dried over magnesium sulphate, filtered and then concentrated to dryness. The residue obtained is recrystallised from acetonitrile (40 cc.) to give (S)-9-nitro-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (3.9 g.) in the form of white crystals melting at 144° C.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:14]([NH2:21])(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1(C)C=CC=CC=1>O>[C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[NH:21][C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCCCCC(N)=O
Reactant: O=C1CCCCC1C1=CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC(=O)NC1=C(C2=CCCCC2)CCCC1

Procedure:
2-(1-Cyclohexenyl)cyclohexanone (17.8 g., 0.1 mole), hexanamide (11.5 g., 0.1 mole), 5.0 g. of a highly acidic resin, Amberlyst 15, and toluene (150 ml) are mixed, stirred and heated at reflux for 16 hours. The water formed in the course of the reaction is azeotroped from the reaction mixture. The hot solution is decanted from the Amberlyst catalyst, the catalyst washed with toluene (200 ml.), and the toluene fractions are combined. Pentane (300 ml.) is added to the toluene solution, the mixture chilled in ice and filtered to remove 3.65 g. of unreacted hexanamide. The orange filtrate is stripped to yield 24 g. of crude product, an oil.