Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[OH:10]/[N:11]=[C:12](/N)\[CH:13]([CH3:15])[CH3:14]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH:13]([C:12]1[N:9]=[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[O:10][N:11]=1)([CH3:15])[CH3:14]
Reactant: N#CN1CCC(O)CC1
Reactant: CC(C)/C(N)=N\O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(O)CC2)n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 4-hydroxypiperidine-1-carbonitrile (0.4 g, 3.1 mmol) in THF (10 mL), (E)-N′-hydroxyisobutyrimidamide (0.35 g, 35 mmol) and ZnCl2 (1M solution in THF) (4.7 mL) were added and stirred at room temperature for 10 h. The reaction mixture was concentrated in vacuo and the resulting crude was dissolved in 4N HCl in ethanol-water (1:1) and stirred at 60-70° C. for 2-3 h. The reaction was quenched by saturated NaHCO3 and the organic layer was separated and concentrated. The residue on column chromatography gave the title compound. (0.280 g, 41.8%)
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].CN(C)C=O.[C:21]([C:23]([C:29]#[N:30])=[C:24](C#N)[C:25]#[N:26])#[N:22]>O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:24]([C:25]#[N:26])=[C:23]([C:29]#[N:30])[C:21]#[N:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: N#CC(C#N)=C(C#N)C#N
Reactant: CCn1c2ccccc2c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(C(C#N)=C(C#N)C#N)ccc21
Temperature: 100 °C

Procedure:
About 1 gram (5.24 × 10-3 3 moles) N-ethyl carbazole and 20 milliliters of dimethylformamide are placed in a 50 milliliter one neck flask equipped with a magnetic stirring bar and a nitrogen inlet tube. The flask is purged of air with nitrogen, the contents of the flask agitated and about 0.67 grams (5.24 × 10-3 moles) of tetracyanoethylene introduced into the flask. Upon the admixture of these materials the contents of the flask turns deep blue. This mixture is heated to 100° C for 20 hours, the contents of the flask poured into 60 milliliters of water at room temperature and the redish brown crystals thereby precipitated isolated from the solution by filtration and washed with ethanol. Yield: 1.13 grams brick red crystals m. p. 239°-241° C. Analysis: calculated, carbon 77, hydrogen 4.08, nitrogen 18.92; actual, carbon 77.24, hydrogen 4.07, nitrogen 18.78.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:23]=[O:24].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:29]([O:28][C:27]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[CH2:19][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:30]([CH3:32])[CH3:31]
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Reactant: CC(C)COc1ccc(C=O)cc1CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)COc1ccc(C=O)cc1Cn1c(-c2ccccc2)cc2ccccc21
Temperature: 0 °C
Yield: 35.5 %

Procedure:
To a solution of 2-phenyl-1H-indole (0.94 g, 4.85 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.19 g, 4.85 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 5 min. 3-(Chloromethyl)-4-isobutoxybenzaldehyde (1.0 g, 4.41 mmol) and sodium iodide (0.73 g, 4.85 mmol) were added to the obtained mixture and the mixture was stirred at the same temperature for 2 hr. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the mixture was washed with 5% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give the title compound (0.60 g, yield 36%) as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:18])[CH:8]=[C:9]([C:13]([O:15]CC)=[O:14])[NH:10]2)=[CH:5][CH:4]=1)=[CH2:2].[OH-].[Na+]>O>[CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:18])[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[NH:10]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc2c(=O)cc(C(=O)OCC)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=Cc1ccc2c(=O)cc(C(=O)O)[nH]c2c1
Yield: 76.3 %

Procedure:
Treatment of ethyl 7-ethenyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.2 g) with sodium hydroxide (0.131 g), as described in Example 1c, gave 7-ethenyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.135 g), mp 281° C. (decomp.), δ (360 MHz, DMSO-d6), 5.47 and 6.00 (2H, 2d, =CH2), 6.61 (1H, s, 3-H), 6.84 (1H, 2d, CH=), 7.54 (1H, dd, 6-H), 7.94 (1H, d, 8-H), 8.05 (1H, d, 5-H) and 11.90 (1H, bs, NH), (Found: C, 63.76; H, 4.48; N, 6.12%, C12H9NO3. 0.6 H2O requires C, 63.77; H, 4.55; N, 6.20%).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][O:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][CH2:11][O:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1)=[O:24]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: Fc1ncccc1C1CCCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1ccc(Oc2ncccc2C2CCCOC2)cc1)c1nc2ccccc2[nH]1
Temperature: 140 °C
Reaction time: 72 h

Procedure:
2-Fluoro-3-(tetrahydro-2H-pyran-3-yl)pyridine (0.10 g, 0.55 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.33 g, 1.38 mmol), and cesium carbonate (0.54 g, 1.66 mmol) were mixed in NMP (2 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 140° C. for 72 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with 1 M aqueous sodium hydroxide (1×), sat. sodium chloride (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-3-yl)pyridin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 400.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([C:14]([O:16]C)=O)=[CH:11][C:10](=[O:18])[C:9]=2[CH:19]=1.[CH3:20][C@@H:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1C=CC=CC=1>[CH3:20][C@@H:21]([NH:28][C:14]([C:12]1[O:13][C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:19][C:9]=2[C:10](=[O:18])[CH:11]=1)=[O:16])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(=O)c2cc(F)ccc2o1
Reactant: C[C@@H](N)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C[C@@H](NC(=O)c1cc(=O)c2cc(F)ccc2o1)c1ccccc1

Procedure:
Sodium methoxide (540 mg, 10.0 mmol) was added to a solution of methyl 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylate (2.22 g, 10.0 mmol, obtained in Example 3 or 4) and (R)-α-methylbenzylamine (1.21 g, 10.0 mmol) in dry benzene (20 ml) and the mixture was refluxed for 2 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][OH:18])[C:10]=1[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23].CCO.C>CN(C)C=O.N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C:10]=1[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCc1c(OCc2ccccc2)c(=O)ccn1CCO
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1c(OCc2ccccc2)c(=O)ccn1CCOC(=O)C(C)C
Yield: 66 %

Procedure:
3-Benzyloxy-2-ethyl-1-(2-hydroxyethyl)pyridin-4-one (0.92 g, 0.003 mole, prepared as described in Example 2), was dissolved in a mixture of 30 ml dimethylformamide and 20 ml of pyridine at room temperature whilst stirring under N2. The solution was added dropwise to a mixture of isobutyryl chloride (1.3 ml, 0.012 mole) in 10 ml of pyridine at 0° C. and the resulting solution was then stirred at room temperature overnight under N2. The reaction was monitored by tlc (silica; 50% EtOH:50% EtOAc). The solution was filtered, the dimethylformamide was removed under high vacuum by rotary evaporation and the oily residue was dissolved in 100 ml of dichloromethane. The solution was washed with 5% w/v aqueous NaHCO3 (3×100 ml) and water (2×100 ml). The organic layer was dried over Na2SO4, filtered and rotary evaporated to give a crude oil. This was treated with activated charcoal in ethyl acetate, filtered and rotary evaporated. The oil produced was purified by means of column chromatography (silica; 50% EtOH:50% EtOAc). Rotary evaporation of the selected samples gave the title compound as an oil in 66% yield, δ(CDCl3), 0.9-1.3 (9H, m), 2.3-2.7 (3H, m), 3.5-4.3 (4H, m), 5.2 (2H, s), 6.2-6.4 (1H, d, 7 Hz), 7.1-7.5 (6H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[C:9](=[O:12])(O)[O-].[Na+]>C(Cl)(Cl)Cl>[NH:1]1[CH:2]([C:7]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:8])[CH2:3][CH2:4][C:9]1=[O:12]
Reactant: O=C([O-])O
Reactant: OCc1ccccn1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1CCC(C(=O)OCc2ccccn2)N1
Temperature: 25 °C
Yield: 60 %

Procedure:
To 90 ml of thionyl chloride was added dropwise 23.5 g of 2-pyrrolidone-5-carboxylic acid with stirring under ice-cooling, and the mixture was stirred for 30 minutes at 40°-50° C. After cooling of the reaction mixture, 200 ml of dry diethyl ether was added to the reaction mixture, and the reaction mixture was allowed to stand overnight in a freezing box. Precipitated crystals were collected by filtration, washed with dry diethyl ether, and dried in a desiccator to obtain 27 g of 2-pyrrolidone-5-carbonyl chloride. The obtained acid chloride was dissolved in 500 ml of dry chloroform, and to the solution were added 13.5 g of 2-pyridylmethanol with stirring at room temperature, and then the reaction mixture was heated under refluxing. After completion of the reaction, to the reaction mixture was added an aqueous sodium bicarbonate solution to make the solution basic at pH 9, and the reaction mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was recrystallized from benzene to obtain 16.2 g of 2-pyridylmethyl 2-pyrrolidone-5-carboxylate. (yield 60.0%)
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in the previous step) and 4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCCCCc1ccc(-c2ccc(C=Cc3ccc(OCC)cc3)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(CCc3ccc(OCC)cc3)cc2)cc1

Procedure:
A solution of 10.6 g of 1-(p-ethoxyphenyl)-2-(4'-n-pentylbiphenyl-4-yl)ethene [obtained by Heck coupling of 4-ethoxystyrene with 4-bromo-4'-n-pentylbiphenyl] in 200 ml of tetrahydrofuran is hydrogenated in the presence of Pd/C until the take-up of H is complete. Customary work-up gives 1-(p-ethoxyphenyl)-2-(4'-n-pentylbiphenyl-4-yl)ethane, mp. 81°, cp. 145°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]=[C:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1.C([O-])=O.[NH4+].O=O>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:37])[C:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: O=O
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a solution of 10 (599 g, 1.16 mol) in glacial acetic acid (11.5 L), ammonium formate (4.0 kg, 62.9 mol) was added and stirred for 30 min. A slurry of Pd on carbon (10%, dry, 300 g) in glacial acetic acid (500 mL) was added to the flask (caution: in a large scale reaction exothermicity may be a problem; rigorous exclusion of oxygen is desirable) and heated at 120° C. for 24 h followed by stirring at room temperature for 48 h. The resulting mixture was filtered through a bed of Celite®. The filtrate was poured slowly into vigorously stirred water (12 L) and the separated solid was filtered and dried. Resulting solid was purified by slurring twice in hot methanol followed by once from ethanol to yield pure 11 as white solid (296 g, 49.2%): mp 126-128° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.01 (br s, 1H), 7.73 (s, 1H), 7.28 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.6 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 6.40 (t, J=2.2 Hz, 1H), 6.27 (d, J=2.2 Hz, 2H), 4.92(dd, J=9.2 and 4.4 Hz, 1H), 3.73 (s, 3H), 3.57 (s, 6H), 3.37 (dd, J=14.8 and 4.3 Hz, 1H) and 3.12 (dd, J=14.8 and 9.4 Hz, 1H); IR (KBr) νmax 3200, 2950, 2850, 1700, 1600, 1500, 1350, 1150, and 850 cm−1; MS (EI) m/z 518[M−H]−, 265, 249, and 113; Anal. (C28H25NO7S) C, H, N.
Reaction SMILES: O[N:2]=[C:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:4]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CCO.[Pd]>[NH2:2][CH:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:4]1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC1CN(c2ccccc2)C(=O)C1=NO
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CN(c2ccccc2)C(=O)C1N

Procedure:
A solution of the product of example 63 in EtOH is hydrogenated with 10% palladium on carbon at 60 psi at 60° C. Filtration and purification of the product on silica gel affords the title compound.
Reaction SMILES: F[C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][N:20](S(C4C=CC(C)=CC=4)(=O)=O)[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH3:41][N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1.[OH-].[K+].C(O)(=O)C>CO.CC(C)=O>[F:13][C:12]1[C:2]([NH:48][CH:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)=[C:3]([CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:11]=1)[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: CN1CCC(N)CC1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(F)c(C(=O)N(C)C)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(F)c(NC4CCN(C)CC4)c(C(=O)N(C)C)c3)cc12
Reaction time: 48 h
Yield: 4.5 %

Procedure:
Into a 5 mL screw-cap vial were added 2,3-Difluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (100 mg, 0.178 mmol) and 1-methyl-piperidin-4-ylamine (102 mg, 0.712 mmol). The vial was sealed and placed in heated block at 120° C. for 48 h. The reaction solution was dissolved in 1:1 methanol/acetone (2 mL total) and treated with 100 μL of 50% w/w aqueous potassium hydroxide for 1 h. Glacial Acetic acid was added to obtain pH 7, then the reaction mixture was concentrated. The residue was purified by reverse-phase HPLC to afford the title compound as a white powder (4 mg, 0.008 mmol, 4% yield). 1H-NMR (500 MHz, d6-DMSO) δ=11.87 (d, J=2 Hz, 1H), 8.49 (d, J=2.5 Hz, 1H), 8.12 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.5 Hz, 1H), 7.61 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 7.54 (dd, J=13.5 Hz, J2=2.0 Hz, 1H), 7.24-7.3 (m, 2H), 7.12 (dd, J1=8.5 Hz, J2=1.0 Hz, 1H), 7.04 (td, J1=7.5 Hz, J2=1.0 Hz, 1H), 4.57 (dd, J1=5 Hz, J2=2.5 Hz, 1H), 3.81 (s, 3H), 3.14 (m, 1H), 3.00 (s, 3H), 2.9 (s, 3H), 3.14 (m, 1H), 2.12 (s, 3H), 1.87 (m, 2H), 1.74 (m, 2H), 1.41 (m, 2H); MS: m/z 502 [MH+].
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#N)=[CH:31][CH:30]=1.C[OH:38]>C1(C)C=CC=CC=1>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:38])=[CH:31][CH:30]=1
Reactant: N#Cc1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Di-iso-butylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of 4-(16-bromohexadecylamino)benzonitrile (11.4 g.) under a nitrogen atmosphere. The temperature rises to 40° C. during the 30 minute addition and then the reaction is then stirred for 1 hour. A solution of methanol in toluene (50 ml., 1:1) was added over 30 minutes and the mixture is poured into vigorously stirred ice-cold aqueous sulfuric acid (50 ml., 5%). After 10 minutes diatomaceous earth (30 g.) is added, the mixture filtered and the organic layer separated. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. The crude product is recrystallized from dichloromethane-hexane to yield 4-(16-bromohexadecylamino)benzaldehyde as a white solid.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]1[CH:12]=[O:13]>CO>[O:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]1[CH2:12][OH:13]
Reactant: O=Cc1cc2cnccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc2cnccc2o1
Reaction time: 1.5 h

Procedure:
NaBH4 (0.26 g, 6.8 mmol) was added to a stirred solution of furo[3,2-c]pyridine-2-carbaldehyde (2.00 g, 13.6 mmol) in anhydrous MeOH (25 mL) at 0° C. After 1.5 h, the reaction was quenched with H2O (20 mL), before being extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated to provide the title compound: m/z (ES+)=150.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4](Br)[CH:3]=1.[CH3:13][O-:14].[Na+].O>CN(C=O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([O:14][CH3:13])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1
Reactant: CC(C)(C)c1cc(Br)cc(Br)c1
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)cc(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of 1,3-dibromo-5-tert-butylbenzene (289 mg, 1 mmol) in DMF (20 mL) were added NaOMe (2 eq) and CuI (0.03 eq). The mixture was stirred at 80° C. for 3 h and then was poured into water and extracted with EA. The combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was evaporated to give compound 14a as solid (200 mg, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH2:9])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20](O)=[O:21])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][NH:9][C:20](=[O:21])[CH:19]([C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH3:23])=[CH:5][CH:4]=1
Reactant: CC(C(=O)O)c1ccc(F)cc1
Reactant: COc1ccc(CCN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C(C)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred mixture of p-methoxyphenethyl amine (3.28 g, 21.7 mmol), p-fluorophenyl propionic acid (3.31 g, 19.7 mmol), and 150 ml anhydrous dichloromethane was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.16 g, 21.7 mmol). The mixture was stirred at ambient temperature for 40 hours and then washed with 1N sodium hydroxide, 1N hydrochloric acid, and saturated sodium chloride, dried, filtered and evaporated to a green solid (5.41 g, 91%). 1H NMR (CDCl3) δ 7.18 (m, 2H); 6.98 (m, 4 H); 6.81 (d, 2 H); 5.32 (br s, 1 H); 3.79 (s, 3 H); 3.44 (q, 2 H); 2.90 (t, 2 H); 2.68 (t, 2 H); 2.39 (t, 2 H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5].[CH3:15][NH:16][CH3:17]>C(O)C.Cl>[CH3:15][N:16]([CH3:17])[CH2:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5]
Reactant: CNC
Reactant: CCCCCCCCNC(=O)CCBr
Agent: Cl
Solvent: CCO
Product: CCCCCCCCNC(=O)CCN(C)C
Reaction time: 72 h
Yield: 83 %

Procedure:
3-Bromo-N-octylpropanamide (21.3 g) was dissolved in ethanol (50 ml) and a 33% solution of dimethylamine in IMS (100 ml) was added. The solution was allowed to stand at 20° for 72 hours then evaporated to give a yellow oil. This oil was dissolved in dilute HCl to give a solution of pH 4 which was washed twice with dichloromethane, basified with dilute aqueous sodium hydroxide solution and extracted with dichloromethane three times. The latter dichloromethane extracts were dried and evaporated to a pale yellow oil. Distillation of the residue gave 3-dimethylamino-N-octylpropanamide as a colourless oil (15.1 g, 83% yield) (bp 135°-8°/0.15mm).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][C:9](=[O:12])[CH:8]=[CH:7]2)[CH2:5][CH2:4][O:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:5]1[C:6]2([CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[CH2:1][CH2:2][O:3][CH2:4]1
Reactant: O=C1C=CC2(CCOCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCC2(CCOCC2)CC1

Procedure:
Under a hydrogen atmosphere 1.30 g (7.82 mmol) 3-oxaspiro[5.5]undec-7-en-9-one were hydrogenated with 0.2 g Pd/C (10%) in 15 ml of ethyl acetate at 50° C. and 3 bar hydrogen pressure for three days. The reaction mixture was suction filtered and evaporated down.