Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](Cl)=[N:8][OH:9])=[N:4][O:5][N:6]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[F:19])[NH2:15].C(=O)(O)[O-].[Na+]>O>[NH2:1][C:2]1[C:3]([C:7](=[N:8][OH:9])[NH:15][C:14]2[CH:16]=[CH:17][C:18]([F:19])=[C:12]([Br:11])[CH:13]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1ccc(F)c(Br)c1
Reactant: Nc1nonc1C(Cl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nonc1C(=NO)Nc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
4-Amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride (33.8 g, 208 mmol) was mixed with water (300 mL). At 60° C., 3-bromo-4-fluoroaniline (Sigma-Aldrich) (43.6 g, 229 mmol, 1.1 equiv.) was added to the suspension with stirring for 10 min. A solution of sodium bicarbonate (26.3 g, 313 mmol, 1.5 equiv.) in water (300 mL) was added over 15 min with stirring at 60° C. After stirring 20 min, LCMS indicated reaction completion. The reaction mixture was then cooled to room temperature and extracted with ethyl acetate (2×300 mL). The combined ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated to give the desired product (65 g, 99%) as an off-white solid, which was used in the subsequent reaction without further purification. C9H7BrFN5O2 (MW 316.09), LCMS (EI) m/e 316/318 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([I:26])=[N:9]2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:41](=[O:42])[C:40]([C:43](O)=[O:44])=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C>CN(C=O)C>[F:25][C:19]1[CH:20]=[C:21]([NH:24][C:43]([C:40]2[C:41](=[O:42])[N:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)[N:37]=[CH:38][CH:39]=2)=[O:44])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[N:9]=[C:10]([I:26])[C:11]=12
Reactant: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-(1-(4-methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (1.50 g, 3.06 mmol; prepared as in Example 7, Step B), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (1.43 g, 6.12 mmol; prepared as in Example 19, Step C), and HOBT-H2O (2.81 g, 18.4 mmol) dissolved in dry DMF (30 mL) was added EDCI (3.52 g, 18.4 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was then partitioned between ethyl acetate (60 mL) and aqueous NH4Cl (100 mL). The organic layer was separated, washed with saturated NaHCO3, dried over NaSO4, and evaporated to dryness. The crude material was triturated with MeOH and the solid removed by filtration, dried to afford the title compound as yellow solid. Yield: 1.93 g, 89%. LRMS (APCI pos) m/e 707.0 (M+H).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)O)=[CH:31][CH:30]=1>C1COCC1>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:35]([C:32]1[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:11])[CH2:3]2
Reactant: O=C(O)C1CN2CCC1CC2
Reactant: COc1ccc(C(O)c2ccccc2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COc1ccc(C(OC(=O)C2CN3CCC2CC3)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 13.5 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (150 mg, 0.78 mmol), EDC (225 mg, 1.17 mmol), and HOBT (180 mg, 1.17 mmol) were dissolved in dry THF (7.5 ml). (4-Methoxyphenyl)(phenyl)methanol (184 mg, 0.86 mmol) and TEA (382 μl, 2.74 mmol) were added, and the resulting reaction was stirred at room temperature for four days. THF was removed under vacuum, and the crude residue was partitioned between EtOAc and water. The organic phase was washed with a sat. NaHCO3, dried over Na2SO4, filtered, and evaporated. The crude was purified by flash chromatography (EtOAc/MeOH=8/2 to EtOAc/MeOH=7:3+1% NH4OH) to give (4-methoxyphenyl)(phenyl)methyl quinuclidine-3-carboxylate (37 mg, mixture of diastereoisomers). The compound was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:19]=[C:18]([C:20]#[C:21][CH2:22][CH2:23][OH:24])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[O:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCCO)oc21
Agent: [Pd]
Solvent: CCO
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCCO)oc21
Temperature: 25 °C
Yield: 85.9 %

Procedure:
N-(4-Chlorobenzyl)-2-(4-hydroxybut-1-ynyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 82, 0.219 g) was dissolved in ethanol (50 mL) with heating and then allowed to cool to room temperature. The mixture was hydrogenated over 10% Pd/C (0.065 g) at 35 psi for 2 h. The reaction mixture was filtered through a Celite pad and the pad was washed with CH2Cl2 (75 mL). The filtrate was concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol, 98/2) to yield 0.190 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 157-160° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.69, 8.52, 7.41-7.32, 6.67, 4.55, 4.43, 3.92, 3.45-3.41, 2.74, 1.73-1.65, 1.53-1.46; 3C NMR (100 MHz, CDCl3) δ 173.6, 165.0, 155.3, 152.6, 140.4, 137.4, 132.8, 128.9, 128.6, 127.5, 116.5, 115.2, 102.7, 62.2, 43.2, 42.5, 37.7, 31.9, 27.8, 23.9; MS (ESI+) m/z 389 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22](C)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 4-(4-bromophenyl)-phenol (4.06 g, 16.3 mmol) in acetone (30 mL) at room temperature, was added 4.5 eq K2CO3 (4.0 M, 18 mL, 73.3 mmol) in water and 4.0 eq lodoethane (5.26 mL, 65.2 mmol). The reaction mixture was stirred overnight, and heated to reflux for 6 hrs. The product was crystallized out of the solution, and filtered. The crude product was recrystallized from hexane to provide ethyl 4-(4-bromophenyl) phenyl ether (4.1 g, 91%) as an white crystal.
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[CH3:22][C:23]([OH:27])([C:25]#[CH:26])[CH3:24].[Cl-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=CC=CC=1.O1CCCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:22][C:23]([CH3:24])([OH:27])[C:25]#[CH:26])=[CH:16][CH:17]=1
Reactant: Fc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: [Pd+2]
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CC(C)(O)Cc1ccc(F)cc1
Yield: 97 %

Procedure:
A 50-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.034 g (0.15 mmol) of palladium (II) acetate, 1.088 g (6 mmol) of dicyclohexylamine and 5 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.157 g (0.3 mmol) of tri-tert-butylphosphonium tetraphenylborate obtained in Example A-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 30° C. for 30 minutes. 0.875 g (5 mmol) of 1-bromo-4-fluorobenzene and 0.505 g (6 mmol) of 2-methyl-3-butyne-2-ol were added, followed by stirring at 30° C. for 17 hours. After the completion of the reaction, 10 ml of tetrahydrofuran, 5 ml of toluene and 15 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.864 g of (4-fluorophenyl)-2-methyl-3-butyne-2-ol (yield: 97 mol % based on 1-bromo-4-fluorobenzene). The identification of the product was made by 1H-NMR and 13C-NMR.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:48]([C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([F:41])[CH:43]=3)(=[O:50])=[O:49])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (340 mg) in tetrahydrofuran (5 mL), 15-crown-5 (330 mg) and 3-fluorobenzenesulfonyl chloride (292 mg) under ice-cooling and the mixture was stirred for 10 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 477 mg, 96%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([I:7])=[C:5]([CH3:8])[NH:4][N:3]=1.[H-].[Na+].[CH:11]1(OS(C)(=O)=O)[CH2:15][CH:14]=[CH:13][CH2:12]1.O>CN(C=O)C>[CH:14]1([N:3]2[C:2]([CH3:1])=[C:6]([I:7])[C:5]([CH3:8])=[N:4]2)[CH2:13][CH:12]=[CH:11][CH2:15]1
Reactant: CS(=O)(=O)OC1CC=CC1
Reactant: Cc1n[nH]c(C)c1I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C2CC=CC2)c(C)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 3,5-dimethyl-4-iodo-1H-pyrazole (5.00 g, 22.5 mmol) in DMF (15 mL) was added NaH (60%, 1.08 g, 27 mmol) in portions and stirred at room temperature for 1 h. To this was added methanesulfonic acid cyclopent-3-enyl ester (4.00 g, 24.7 mmol) and heated at 60° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate (60 mL). The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography using 5-10% ethyl acetate in hexane to give the title compound as an oil. 1H NMR (300 MHz, CDCl3): δ=5.75 (s, 2H), 4.97 (m, 1H), 2.79 (d, 4H, J=7.2 Hz), 2.28 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:29]4[CH2:28][CH2:27][C:26]([C:23]5[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=5)([OH:32])[CH2:31][CH2:30]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Product: OC1(c2ccc(F)cc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Yield: 27 %

Procedure:
Using a procedure similar to that described in example 21 except starting with 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (described in example 1i) and 4-(4-fluorophenyl)-4hydroxypiperidine, the title compound hydrochloride salt was obtained in 27% yield as a white powder, mp 280°-281° C. elemental Analysis for C27H25ClFNO.HCl.0.5H2O: Calculated: C, 67.64; H, 5.68; N, 2.92 Found: C, 67.70; H, 5.40; N, 2.84.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[C:38]4[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=4[S:40][CH:41]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1csc2ccccc12
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2csc3ccccc23)CC1
Yield: 44.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.50 g) as starting compound, potassium carbonate (0.75 g) and 6-bromo-1-(3-benzo[b]thienyl)-1-hexanone (0.42 g) were reacted and treated in the same manner as in Example 172 to give 0.32 g of 4-amino-5-chloro-N-((1-(6-(3-benzo[b]thienyl)-6-oxohexyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18](B(O)O)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=23)=[C:19]2[CH2:24][CH2:23][CH2:22][N:20]2[N:21]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: Brc1cnn2cccnc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc(-c2nn3c(c2-c2cnn4cccnc24)CCC3)nc1
Yield: 4.5 %

Procedure:
Weigh into a round bottom flask 3-bromopyrazolo[1,5-a]pyrimidine (Lynch et al. Can. J. Chem. 1975, 53, 119-122; 0.095 g, 0.48 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 0.10 g, 0.44 mmol), triphenylphosphine (Aldrich; 0.007 g, 0.027 mmol) and tris(dibenzylideneacetone)dipalladium(0) (Aldrich; 0.015 g, 0.016 mmol). Add p-dioxane (6 ml) and 2.0M aqueous potassium carbonate (2 mL). Stir and reflux under nitrogen for 6 h. Dilute with ethyl acetate, separate the organic layer, concentrate under reduced pressure, and chromatograph on flash silica using neat acetonitrile. Purify on a preparative reverse phase C-18 high-performance chromatography column using a gradient from 5% to 100% acetonitrile in 0.03% aqueous hydrochloric acid. Concentrate the pure fractions under reduced pressure, dissolve the residue in distilled water, and make basic by adding 1.0M aqueous sodium hydroxide. Extract with dichloromethane, dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 6 mg (4.5%) of the title compound as a yellow solid. TOF MS ES+ exact mass calculated for C17H15N6 (M+1): m/z=303.1358; Found: 303.1371. 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J=2 Hz, 1H), 8.64 (d, J=2 Hz, 1H), 8.41 (dd, J=4, 2 Hz, 1H), 8.31 (s, 1H), 7.70 (m, 2H), 7.21 (m, 1H), 6.79 (dd, J=7, 4 Hz, 1H), 4.30 (t, J=7 Hz, 2H), 3.10 (t, J=8 Hz, 2H), 2.68 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8]C(C)(C)C)=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19].[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)NCc1cc(C(=O)OC(C)(C)C)ccc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)NCc1cc(C(=O)O)ccc1N
Reaction time: 12 h

Procedure:
To a solution of t-butyl 4-amino-3-[(N-methylacetylamino)methyl]benzoate (2.13 g, 7.65 mmole) in CH2Cl2 (150 mL) at RT was added TFA (30 mL). After 12 hr, the reaction solution was concentrated to an oil and dried under high vacuum overnight. The resulting residue was washed with hexanes and Et2O to afford the title compound (2.56 g, 7.60 mmole) as an off-white solid. This compound was used without further purification: MS (ES) m/e 223 (M+H-TFA)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:11]C(=O)C(C)(C)C)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[NH2:11]
Reactant: CC(C)(C)C(=O)Nc1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A mixture of N-(3-fluoro-4-nitro-phenyl)-2,2-dimethyl-propionamide (87.0 g, 0.36 mol) in CH2Cl2 (400 mL) and 6N hydrochloric acid (800 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with 1000 mL of ethyl acetate and potassium carbonate (500.0 g) was added portion wise. The aqueous solution was separated and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed by evaporation under reduced pressure; the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 30:1) to afford 3-fluoro-4-nitroaniline (56.0 g, 99%). 1H NMR (300 MHz, CDCl3) δ 8.07 (t, J=8.7 Hz, 1H), 7.86 (dd, J=2.1, 13.2 Hz 1H), 7.59 (brs, 2H), 7.22 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]#[N:13])=[CH:7][CH2:6][CH2:5]2>CCO.Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][NH2:13])[CH2:7][CH2:6][CH2:5]2
Reactant: N#CC1=CCCc2cc(Cl)ccc21
Agent: Cl
Solvent: CCO
Product: NCC1CCCc2cc(Cl)ccc21

Procedure:
The product from Example 46 was catalytically reduced with Pt2O at 4 atms. pressure in EtOH and HCl, the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)=[C:7]([C:18]([NH:20][CH3:21])=[O:19])[C:6]=2[CH:22]=1.[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:25])=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)=[C:7]([C:18]([NH:20][CH3:21])=[O:19])[C:6]=2[CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(C#N)cc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.7 %

Procedure:
A solution of 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (200 mg, 0.44 mmol), K2CO3 (124 mg, 1.89 mmol) in DMF (5 mL) was stirred at RT and CH3I (182 mg, 1.32 mmol) was added dropwise. The reaction was stirred at RT for 3 h. The reaction was concentrated, washed with H2O and filtered to give 5-bromo-2-(4-cyanophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (150 mg, yield: 73%). 1H-NMR (CDCl3, 400 MHz) δ 8.09 (s, 1H), 8.07 (d, J=8.0 Hz, 2H), 7.78 (s, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 5.88 (s, 1H), 3.34 (s, 3H), 3.10 (s, 3H), 3.05 (d, J=5.2 Hz, 3H). MS (M+H)+: 462/464.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].C([O:15][C:16](=O)[C:17]([C:29]#[N:30])=[CH:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=1)C>C1COCC1>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:18]2[CH:17]([C:29]#[N:30])[C:16](=[O:15])[O:1][C:2]3[C:10]=2[CH:9]=[CH:8][C:7]2=[N:6][CH:5]=[CH:4][C:3]=32)[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=1
Reactant: CCOC(=O)C(C#N)=Cc1cc(OC)cc(OC)c1
Reactant: Oc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C2=c3ccc4c(c3OC(=O)C2C#N)C=CN=4)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.1 %

Procedure:
To a solution of 3,5-dimethoxybenzaldehyde (1.35 g, 8.12 mmol) and ethyl cyanoacetate (0.92 ml, 8.1 mmol) in ethanol (10 mL) was added piperidine (0.4 mL, 4 mmol). The mixture was stirred at room temperature for approximately 2 h. A precipitate formed, which was collected by filtration and dried to yield approximately 2.12 g of a white solid, which was used directly in the next step. To a solution of 4-hydroxyindole (250 mg, 1.91 mmol) in THF (10 mL) was added sodium hydride (153 mg, 3.80 mmol, 60%) and the mixture was stirred at room temperature for approximately 10 min. To the mixture was added a solution of 3-(3,5-dimethoxyphenyl)-2-cyano-acrylic acid ethyl ester (500 mg, 1.91 mmol, prepared as described above) in THF (2 mL). The mixture was heated at approximately 60° C. overnight. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel, EtOAc:hexane, 1:2), yielding 7 mg (1.1%) of the title compound. 1H NMR (CDCl3): 8.64 (brs, 1H), 7.35-7.24 (m, 2H), 7.19-7.16 (m, 1H), 7.04 (s, 1H), 6.65-6.59 (m, 3H), 3.85 (s, 6H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:36])[CH2:23][CH:24]([NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:25](OC)=[O:26])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([C:22](=[O:36])[CH2:23][CH:24]([NH:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][OH:26])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(CC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)NC(=O)C(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NC(CO)CC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 1.5 h

Procedure:
106 mg (0.218 mmol) of methyl 4-[4-(5H-dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-[(2,2-dimethylpropanoyl)amino]-4-oxobutanoate was dissolved in 3 ml of tetrahydrofuran. 5.7 mg (0.261 mmol) of lithium borohydride was added to the obtained solution at 0° C. The reaction mixture was stirred for 1.5 hours and then saturated aqueous ammonium chloride solution was added thereto. After extracting with ethyl acetate 3 times, the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound.