Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:13]=[C:12]3[C:7]([C:8]([CH:15]([O:17][CH2:18][C:19]4([C:32]5[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=5)[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]4)[CH3:16])=[CH:9][C:10]([CH3:14])=[CH:11]3)=[N:6]2)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[CH:1]1([CH2:4][N:5]2[CH:13]=[C:12]3[C:7]([C:8]([CH:15]([O:17][CH2:18][C:19]4([C:32]5[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=5)[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH3:16])=[CH:9][C:10]([CH3:14])=[CH:11]3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2nn(CC3CC3)cc2c1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C)CC2)c2nn(CC3CC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl 4-((1-(2-(cyclopropylmethyl)-5-methyl-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (15 mg, 0.03 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2 M ammonia in methanol and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (9 mg, 0.14 mmol) and formalin (79 μL). After 5 min, the reaction was treated with a few drops of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was concentrated and purified by flash chromatography on silica gel (10% methanolic ammonia/methylene chloride) to afford 5 mg (40%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.32-7.34 (m, 2H), 7.23 (m, 1H), 6.99-7.02 (m, 2H), 6.66 (m, 1H), 4.94 (q, J=6.4 Hz, 1H), 4.22-4.24 (m, 2H), 3.34-3.41 (m, 2H), 2.57 (m, 2H), 2.29 (s, 3H), 2.21 (s, 3H), 2.09-2.25 (m, 6H), 2.01-2.04 (m, 1H), 1.44 (d, J=6.4 Hz, 3H), 0.64 (m, 2H), 0.40-0.43 (m, 2H). Mass spec.: 436.53(MH)+.
Reaction SMILES: [NH:1]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH:2]1[CH3:3].[OH-].[Na+].[C:14](Cl)([Cl:16])=[O:15]>C(OCC)C.O>[Cl:16][C:14]([N:1]1[CH:11]2[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:5][CH2:4][CH:2]1[CH3:3])=[O:15]
Reactant: O=C(Cl)Cl
Reactant: CC1CCC2CCCCC2N1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC1CCC2CCCCC2N1C(=O)Cl

Procedure:
A mixture of 15 g decahydro-quinaldine dissolved in 200 ml of diethylether and 4 g of sodium hydroxide in 50 ml of water is reacted while stirring and cooling at -5° to 0° with 10 g of phosgene. An ethereal solution of 1-chlorocarbonyl-2-methyl-decahydro-quinoline is obtained. When an aqueous solution of 8.4 g of sodium ethylmercaptide is added to the ethereal solution at room temperature with stirring, 16 g of an almost colorless oil are obtained. The physical constants of this oil coincide with those of the compound of Example 1.
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[SH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].CC(C)([O-])C.[K+].Cl>CN(C=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([C:5]2[CH:16]=[CH:17][C:2]([S:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[N:3][CH:4]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(F)cc1)c1ccc(Cl)nc1
Reactant: O=C(O)CCS
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Temperature: 60 °C
Yield: 66.3 %

Procedure:
To a solution of 6-chloro-N-(4-fluoro-phenyl)-nicotinamide (0.20 g, 0.80 mmol) in 10 mL of DMF was added 3-mercaptopropionic acid (0.10 mL, 1.2 mmol) and potassium tert-butoxide (0.31 g, 2.8 mmol) and the mixture heated to 60° C. After 9 h the reaction mixture was poured into ice water, HCl (1 M, aq) added to adjust to pH 6, and the solids removed via filtration. The filtrate was then taken to pH 10 with NaOH (4M, aq) and extracted with ethyl acetate. HCl (6M, aq) was then added to the filtrate to adjust the pH to 4 and extracted with ethyl acetate, dried over sodium sulfate, and the solvents removed in vacuo to yield a white solid. Purification by recrystallization using ethyl acetate gave 0.17 g (66%) of the titled product as a white solid; MS (EI) m/z 319.20 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][C:19](=[CH:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H][H]>[Pd].C(OCC)(=O)C>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:3]([OH:8])([C:4]([F:7])([F:5])[F:6])[C:2]([F:1])([F:32])[F:33])=[CH:10][CH:11]=3)[CH2:21][CH2:20]2)=[CH:28][CH:27]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C=C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Yield: 62.6 %

Procedure:
A stirred mixture of 1,1,1,3,3,3-hexafluoro-2-(4-((4-(4-nitrobenzylidene)piperidin-1-yl)methyl)phenyl)propan-2-ol (15.39 mmol, 7.3 g) and palladium on carbon (5%) (0.308 mmol, 0.328 g) in ethyl acetate was hydrogenated at 3 bar until the desired amount of hydrogen was consumed. The mixture was filtered through celite washing with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was chromatographed on silica (eluting with a gradient of dichloromethane to ethyl acetate) to give the title compound (4.3 g). MS (ESI) m/z 447.2 [M+H]+
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl.C(N(CC)CC)C.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.[CH3:31][C:32]1[CH:37]=[C:36]([CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42](=O)[NH:41][N:40]=2)[CH:35]=[CH:34][N:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:42]2[C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:39]([CH2:38][C:36]3[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=3)=[N:40][N:41]=2)=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1cc(Cc2n[nH]c(=O)c3ccccc23)ccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cc2nnc(Nc3ccc(Cl)cc3)c3ccccc23)ccn1
Temperature: 200 °C
Reaction time: 16 h

Procedure:
A mixture of 910 mg (6.36 mmol) phosphorus pentoxide, 876 mg (6.36 mmol) triethylamine hydrochloride, and 812 mg (6.36 mmol) 4-chloroaniline is heated at 200° C. until a homogeneous melt has formed. To the melt, 400 g (1.59 mmol) 4-[(2-methyl-pyridin-4-yl)-methyl]-1(2H)-phthalazinone is added and the reaction mixture stirred for a further 16 h at 200° C. The cooled reaction mixture is distributed with thorough stirring and use of an ultrasonic bath between a dichloromethane/methanol mixture (about 20:1) and saturated aqueous sodium carbonate solution. The organic phase washed with water and brine is dried over anhydrous sodium sulfate, evaporated under vacuum, and the residue purified by means of flash chromatography on silica gel with particle size 0.04-0.06 mm, using an acetate/methanol mixture (19:1). Title compound is obtained after evaporation of the product-containing fractions under vacuum and crystallization of the residue from acetonitrile; m.p. 158-159° C.; ESI-MS: (M+H)+=361. The starting material is prepared as follows:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (74 mg, 86%), MS (ISP) m/z=345.4 [(M+H)+], mp 236.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Cl:17][C:18]1[CH:19]=[C:20]([OH:27])[CH:21]=[N:22][C:23]=1[CH:24]1[CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([O:27][C:20]2[CH:21]=[N:22][C:23]([CH:24]3[CH2:26][CH2:25]3)=[C:18]([Cl:17])[CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: Oc1cnc(C2CC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 59, 35.7 g, 143.86 mmol) in DMSO (97.6 mL) was added 5-chloro-6-cyclopropylpyridin-3-ol (Preparation 69, 24.4 g, 143.86 mmol) and stirred at room temperature until a solution obtained. Potassium carbonate (49.7 g, 359.65 mmol) was added portion wise maintaining the internal temperature at 15-25° C. with a cold water jacket. The reaction mixture was stirred at room temperature for 12 hours, cold water charged and the resulting slurry stirred for 90 minutes. The mixture was filtered, washed with water and dried to give the title compound as a pale yellow solid (54.0 g, 94%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)(=[O:10])[CH:8]=[CH2:9].[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:49]=[CH:48][C:37]([C:38]([O:40][C:41]2[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=2)=[O:39])=[CH:36][CH:35]=1)(=[O:27])[CH:25]=[CH2:26].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([C:38]([O:40][C:41]2[CH:46]=[CH:45][C:44]([O:20][C:19](=[O:21])[C:18]3[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][O:11][C:7](=[O:10])[CH:8]=[CH2:9])=[CH:23][CH:22]=3)=[CH:43][CH:42]=2)=[O:39])=[CH:48][CH:49]=1)(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)OCCCCOc1ccc(C(=O)Oc2ccc(O)cc2)cc1
Reactant: C=CC(=O)OCCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OCCOC(=O)C=C)cc3)cc2)cc1
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
Oxalyl chloride (10 ml) is added at 0° C. to 4-(2'-acryloxyethoxy)-benzoic acid (4.3 g; 16.3 mmol), and the mixture is stirred until the evolution of gas subsides (30 min). The excess oxalyl chloride is removed by distillation in a water-pump vacuum, the acid chloride is taken up in toluene (10 ml), the toluene solution is added at 0° C. to a solution of (3) (5.8 g; 16.3 mmol) in pyridine (10 ml) and toluene (5 ml), and the mixture is subsequently stirred at room temperature for 13 hours. The reaction mixture is then transferred into water (200 ml), and the mixture is extracted twice with dichloromethane (50 ml each time). The organic extracts are dried using calcium chloride, hydroquinone (50 mg) is added to the filtrate, and the mixture is evaporated in a water-pump vacuum. The residue is chromatographed on silica gel (toluene/ethyl acetate (5:1), giving 7.8 g (83%) of (4).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]=2[N:19]=1.FC(F)(F)C(O)=O.[Na].[OH-]>ClCCl>[CH3:1][C:2]1[N:3]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:4]2[C:9]([CH3:10])=[C:8]([CH3:11])[N:7]=[C:6]([O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:5]=2[N:19]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCNC(=O)OC(C)(C)C)c2c1C
Agent: [Na]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCCCN)c2c1C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A solution of tert-butyl 4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butylcarbamate (6.70 g, 15.8 mmol) in dichloromethane (50 mL) was slowly added to a chilled (0° C.) mixture of trifluoroacetic acid (60 mL) and dichloromethane (100 mL). The reaction mixture was allowed to warn to ambient temperature and then left overnight. The reaction mixtures was concentrated under reduced pressure to provide a brown oil. The oil was dissolved in dichloromethane and the solution was made basic (pH 14) with 5% aqueous sodium;hydroxide. The layers were separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide 4.50 g of 4-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)butylamine as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.C(N(CC)CC)C.C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 92.3 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g), triethylamine (9.42 g), acetic acid (0.75 g) and 1,2-dichloroethane (24 g) was heated under reflux for 8 hours. The reaction mixture was washed with water (24 g). The organic layer was separated and treated as in Example 4 to give the compound (I) (16.2 g).
Reaction SMILES: O[Li].O.[C:4]12([C:14]3[CH:15]=[C:16]([C:22]4[CH:33]=[CH:32][C:25](/[CH:26]=[CH:27]/[C:28]([O:30]C)=[O:29])=[CH:24][CH:23]=4)[CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2>C1COCC1.O>[C:4]12([C:14]3[CH:15]=[C:16]([C:22]4[CH:23]=[CH:24][C:25](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:32][CH:33]=4)[CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(/C=C/C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
455 mg (10.8 mmol) of LiOH.H2O were dissolved in 90 ml of THF:H2O 1:1; 873 mg (2.17 mmol) of methyl E-4(3-(1-adamantyl)-4-methoxyphenyl)cinnamate were added and the solution thus obtained was kept under stirring at room temperature for 2 days. The THF was evaporated, acidified with 2N HCl and the white precipitate was filtered. The solid was washed with AcOEt and Et2O, to obtain 792 mg (94%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:17])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:17])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 25 °C

Procedure:
A solution of 5-bromo-2-methylpyridine (10 g, 58.13 mmol) and meta-chloroperbenzoic acid (mCPBA, 30 g, 174.39 mmol) in CHCl3 (160 mL) was heated at 60° C. for 16 h. The mixture was cooled to rt and neutralized with satd. NaHCO3. The resulting mixture was extracted with DCM. The organic layers were combined and washed with brine and dried (MgSO4). The solvent was removed in vacuo. The crude was purified by silica gel chromatography (EtOAc/hexanes) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[C:33]([N:40]1[CH2:48][CH2:47][CH:43]([C:44](O)=[O:45])[CH2:42][CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CCN(C(C)C)C(C)C>CN(C=O)C>[C:36]([O:35][C:33]([N:40]1[CH2:48][CH2:47][CH:43]([C:44](=[O:45])[NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[CH2:42][CH2:41]1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(=O)c1ccc(N)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
To a solution of 4-aminoacetophenone (6.76 g, 50 mmol) in DMF (250 ml) were added TOTU (16.40 g, 50 mmol), boc-isonipecotic acid (11.46 g, 50 mmol) and DIPEA (8.6 ml, 50 mmol). The reaction mixture was stirred at ambient temperature for 12 h. The solvent was removed in vacuo. The residue was redissolved in ethyl acetate (250 ml) and washed with sat. sodium hydrogen carbonate solution (2×50 ml), hydrochloric acid (1 N, 50 ml) and brine (50 ml). The organic phase was dried over sodium sulfate, evaporated and recrystallized from ethyl acetate. The product was obtained as white crystalline solid (yield: 12.2 g, 70%).
Reaction SMILES: [C:1]([CH:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:14])([O:3][CH2:4][CH3:5])=[O:2].[I-].[Na+].[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1.O>[C:1]([C:6]1([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:14])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1CCCCCCC1=O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(C(=O)OCC)CCCCCCC1=O
Temperature: 110 °C

Procedure:
A solution of 2-carboethoxy-cyclooctanone (92.2 g, 0.5 mole) in toluene (1.6 l) is treated with sodium iodide (1 g) and 60% sodium hydride in mineral oil (23.3 g, 0.58 mole). The mixture is heated at 110° C. The mixture is treated with ethyl α-bromoacetate (98.0 g, 0.58 mole) dropwise and the mixture is warmed to 65° C. for 18 hours. The mixture is cooled and water (500 ml) was added. The layers are separated and the aqueous is extracted with toluene (2×1 l). The extracts are dried (MgSO4) and filtered. The filtrate is concentrated at reduced pressure and distilled to yield pure 2-carboethoxy-2-carboethoxymethylcyclooctanone with a bp of 193°-195° C. at 16 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH:28]=[C:27]([C:30]3[C:38]4[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=4)[NH:32][CH:31]=3)[CH2:26][CH2:25]2)[C:18](=[O:20])[CH3:19])[CH2:11][CH2:10]1.C([SiH](CC)CC)C.[ClH:47]>FC(F)(F)C(O)=O>[ClH:47].[ClH:47].[ClH:47].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[C:38]4[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=4)[NH:32][CH:31]=3)[CH2:26][CH2:25]2)[C:18](=[O:20])[CH3:19])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCN(CCCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)C(C)=O)CC1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1N1CCN(CCN(CCCN2CCC(c3c[nH]c4cc(F)ccc34)CC2)C(C)=O)CC1

Procedure:
Following the same procedures reported in the EXAMPLE 4, the double bond reduction of the compound of EXAMPLE 8 (0.307 mmol) with triethylsilane (0.337 mmol) in trifluoroacetic acid followed by treatment with hydrochloric acid gave the title compound.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].[CH:17](=O)[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>C(O)C.Cl.C(O)(C)C.O>[CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH:9]=[CH:17][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCc1sc(C(C)=O)cc1-c1ccccc1
Reactant: O=Cc1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CC(C)O
Product: CCc1sc(C(=O)C=Cc2ccc(C=O)cc2)cc1-c1ccccc1
Yield: 31 %

Procedure:
A solution of 1-(5-ethyl-4-phenyl-thiophen-2-yl)-ethanone (600 mg, 2.61 mmol) and terephthalaldehyde (874 mg, 6.51 mmol) in ethanol (10 mL) and 5 N HCl in isopropanol (5 mL) is stirred at rt for 3 days. The reaction mixture is diluted with water and extracted with diethyl ether. The organic extract is washed with water and sat. aq. NaHCO3 solution and the solvent is evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 4-[3-(5-ethyl-4-phenyl-thiophen-2-yl)-3-oxo-propenyl]-benzaldehyde (280 mg) as a yellow solid, LC-MS: tR=1.14 min, [M+1]+=347.14, 1H NMR (CDCl3): δ 10.05 (s, 1H), 7.95-7.88 (m, 2H), 7.84-7.77 (m, 3H), 7.52-7.35 (m, 5H), 2.96 (q, J=7.6 Hz, 2H), 1.35 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=[C:15]([Br:26])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:6]=1.C1N2CN3CN(C2)CN1C3.Cl.[C:38](O)(C(F)(F)F)=[O:39]>>[Br:1][C:2]1[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=[C:15]([Br:26])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:12]([CH3:13])[CH3:14])[C:8]([OH:11])=[C:9]([CH:10]=1)[CH:38]=[O:39]
Reactant: CC(C)c1cc(Oc2c(Br)cc([N+](=O)[O-])c(C(F)(F)F)c2Br)ccc1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CC(C)c1cc(Oc2c(Br)cc([N+](=O)[O-])c(C(F)(F)F)c2Br)cc(C=O)c1O
Temperature: 98 °C
Reaction time: 5 h
Yield: 57 %

Procedure:
4-(2,6-dibromo-4-nitro-3-trifluoromethylphenoxy)-2-isopropylphenol of Part 11C (220 mg, 0.44 mmol) was dissolved in TFA (3 mL) and hexamethylenetetramine (154 mg, 1.1 mmol) was added to the reaction. The reaction mixture was heated at 98° C. for 12 hours, cooled down and 1N HCl (4 mL) was added. The reaction mixture was stirred for 5 hours at room temperature, extracted with EtOAc, washed with H2O, NaHCO3 and brine. The organic layer was dried by MgSO4 and concentrated. The residue was purified on column (silica gel, gradient elution with n-heptane/EtOAc) to give 130 mg (57%) of 5-(2,6-dibromo-4-nitro-3-trifluoromethylphenoxy)-2-hydroxy-3-isopropylbenzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(=O)C>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(C(=O)O)n1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cccc(N)n1

Procedure:
6-Aminopyridine-2-carboxylic acid (5.0 g, 36 mmol) was dissolved in 50 ml of MeOH. To this was added acetyl chloride (9.0 ml, 126 mmol) in 50 ml of MeOH. The reaction was heated to reflux overnight. Concentrate to an orange oil and partition with EtOAc and water. The organic portions were washed with brine, dried (MgSO4) and concentrated to a yellow solid.