Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:34][CH3:35])[CH:10]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:34][CH3:35])[CH:10]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Reactant: CNCCN(C)C
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 140 °C
Yield: 80.5 %

Procedure:
N1,N1,N2-Trimethylethane-1,2-diamine (83 mg, 0.82 mmol) was added to a mixture of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 68, 409 mg, 0.74 mmol), DIPEA (0.259 mL, 1.48 mmol) and DMA (3 mL). The resulting mixture was heated in a microwave at 140° C. for 0.5 h. Part-purification was achieved by ion exchange chromatography, using an SCX column (20 g) and eluting with 0.35 M methanolic ammonia. Appropriate fractions were concentrated in vacuo to provide an orange/brown gum. This gum was triturated with ethanol (15 mL) to give a solid which was collected by filtration and dried under vacuum to give the title compound (275 mg, 80%) as an orange solid; 1H NMR: 2.18 (6H, s), 2.45-2.55 (2H, m), 2.87 (3H, s), 3.25-3.30 (2H, m), 3.97 (3H, s), 6.87 (1H, s), 7.08 (1H, t), 7.18 (1H, t), 7.29 (1H, d), 7.46 (1H, d), 8.03 (1H, s), 8.33 (3H, dd), 8.66 (1H, s), 11.80 (1H, s); m/z: ES+ MH+ 462.34.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:10]=[C:11]([C:20]#[N:21])[C:12](=[CH:15][C:16]=1[N+:17]([O-])=[O:18])[C:13]#[N:14])([C:3](OCC)=[O:4])=[O:2].[H][H]>CN(C)C=O.[Pd]>[C:20]([C:11]1[CH:10]=[C:9]2[C:16](=[CH:15][C:12]=1[C:13]#[N:14])[N:17]([OH:18])[C:3](=[O:4])[C:1](=[O:2])[NH:8]2)#[N:21]
Reactant: [H][H]
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)c(C#N)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Product: N#Cc1cc2[nH]c(=O)c(=O)n(O)c2cc1C#N
Yield: 57.9 %

Procedure:
A solution of 0.8 g (3.03 mmol) 4-ethoxalylamino-5-nitrophthalonitrile in 50 ml dimethylformamide was hydrogenated at atm. pressure by using 25 mg 5% Pd-C as a catalyst. When the hydrogen uptake had ceased, the reaction mixture was filtered and evaporated in vacuo. The residue was recrystallized (dimethylformamide-water) to give 0.4 g (66%) of 6,7-dicyano-1-hydroxy-quinoxaline-2,3(1H,4H)-dione. M.p. decomp. 1H-NMR (DMSO-d6): 7.97 (1H, s), 7.57 (1H, s). MS (m/e): 228 (M+, 80%).
Reaction SMILES: N1[CH:5]=[CH:4][N:3]=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[OH2:14]>C(Cl)Cl>[C:7]([Si:10]([CH3:12])([CH3:11])[O:14][CH2:5][CH2:4][NH2:3])([CH3:9])([CH3:8])[CH3:6]
Reactant: O
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN
Reaction time: 1 h
Yield: 30 %

Procedure:
1.97 mL (32.74 mmol) of 156 and 2.455 g (36.06 mmol) of imidazole were dissolved in 15 mL of CH2Cl2 and 5.18 g (34.37 mmol) of TBSCl was carefully added. After 1 h at room temperature, the mixture was concentrated and loaded on a silica gel flash chromatographic column. Elution with a mixture of 20:1 (v/v) CH2Cl2/methanol containing 0.5% (by volume) triethylamine failed to afford pure product. The eluted mixture was dissolved in water, extracted with diethyl ether (3×) and dried over sodium sulfate. Removal of the solvent yielded 1.73 g (30%) of 157 as a brown oil. 1H NMR (400 MHz, CDCl3) δ 0.06 (s, 6H), 0.90 (s, 9H), 1.74 (br s, 2H), 2.77 (t, J=5.1, 2H), 3.63 (t, J=5.2, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2C(=O)[C:12](=[O:15])[C:11]3([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:10]=2)=[CH:5][CH:4]=1.[NH2:21][C@H:22]([CH2:26][OH:27])[CH:23]([CH3:25])[CH3:24].C(OCC)(=[O:30])C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:10][C:11]2([C:12]([NH:21][C@H:22]([CH2:26][OH:27])[CH:23]([CH3:25])[CH3:24])=[O:15])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:30])=[CH:7][CH:8]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(C2=NC3(CCCCC3)C(=O)C2=O)cc1
Reactant: CC(C)[C@H](N)CO
Product: COc1ccc(C(=O)NC2(C(=O)N[C@H](CO)C(C)C)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 66.7 %

Procedure:
260 mg (1.00 mmol) of 2-(4-methoxyphenyl)-3-oxo-1-azaspiro[4.5]dec-1-en-4-one was added to a solution of 252 mg (2.45 mmol) of L-valinol in 5 ml of ethyl acetate, and the mixture was stirred at room temperature for 4 days. The reaction solution was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 243.5 mg (66.7%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[C:11](Cl)=[O:12])[O:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[CH3:21][NH:22][CH3:23].O>C(OCC)(=O)C>[CH3:21][N:22]([CH3:23])[C:11]([CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:5]21[O:4][CH2:3][CH2:2][O:1]2)=[O:12]
Reactant: O=C(Cl)C1CCCCC12OCCO2
Reactant: CNC
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C1CCCCC12OCCO2
Temperature: 20 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a 1 M solution of 1,4-dioxa-spiro[4.5]decane-6-carbonyl chloride in toluene (1 mL, 1 mmol) was added at 0° C. a 7.9 M solution of dimethylamine in water (1.27 mL, 10 mmol). The mixture was stirred at 20° C. for 1 h, then diluted with ethyl acetate (40 mL), and washed successively with water (10 mL), saturated aqueous sodium carbonate solution (10 mL), 1 N hydrochloric acid, and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the title compound (69 mg, 32%) as colorless oil. MS ISP (m/e): 214.3 (100) [(M+H)+].
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[F:9][C:10]1[CH:15]=[CH:14][C:13](/[C:16](=[N:18]/[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][O:22][C:23]3=[O:28])/[CH3:17])=[CH:12][CH:11]=1.[CH3:29][CH2:30][O-:31].[Na+].C(OCC)(=O)C>C(OCC)(=O)CC>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([CH3:17])[CH:7]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=3)[C:30](=[O:31])[C:29]3[C:24]([C:23]([O:22][CH2:21][CH3:20])=[O:28])=[CH:25][CH:26]=[CH:27][C:19]=3[NH:18]2)=[CH:14][CH:15]=1
Reactant: C/C(=N\c1cccc2c1COC2=O)c1ccc(F)cc1
Reactant: Cn1ccnc1C=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(C)(c1ccc(F)cc1)N2
Temperature: 30 °C
Reaction time: 3 h
Yield: 8 %

Procedure:
To a solution of 1-methyl-1H-imidazole-2-carbaldehyde (580 mg, 5.2 mmol), and (E)-4-(1-(4-fluorophenyl)ethylideneamino)isobenzofuran-1(3H)-one (1 g, 3.7 mmol) in ethyl propionate (20 ml) was added rapidly EtONa [sodium (340 mg, 14.8 mmol) in 8 mL ethanol] at 0° C., then the mixture was stirred at 30° C. for 3 hr. The resulting mixture was added ethyl acetate (150 mL) and washed with water (25 mL×3), the organic layers were combined and evaporated to dryness to give the crude product, which was purified by column chromatography (silica gel, dichloromethane:methanol=200:1 to 50:1) to afford the title compound as a red solid (120 mg, yield 8%). LC-MS (ESI) m/z: 408 (M+1)+
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:35])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:16][CH2:15]2)=[O:11])=[C:4]([CH3:36])[CH:3]=1.CN(C)[CH:39]=[O:40].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:71][OH:72]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:71][O:72][C:39](=[O:40])[C:2]1[CH:3]=[C:4]([CH3:36])[C:5]([NH:9][C:10](=[O:11])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:35])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:16][CH2:15]2)=[CH:6][C:7]=1[CH3:8]
Reactant: CN(C)C=O
Reactant: Cc1cc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c(C)cc1I
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cc(C)c(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of biphenyl-2-ylcarbamic acid 1-[2-(4-iodo-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (56 g, 94 mmol) in a 5:1 v/v mixture of N,N-dimethylformamide and methanol (600 mL) were added diispropylethylamine (49 mL, 281 mmol), 1,3-bis(diphenylphosphino)propane (3.9 g, 9.4 mmol) and palladium(II) acetate (2.1 g, 9.4 mmol). The resulting mixture was purged with carbon monoxide and then stirred overnight at 70° C. to 80° C. under a carbon monoxide atmosphere (balloon pressure). The reaction mixture was concentrated under vacuum and the residue was dissolved in dichloromethane (500 mL). This mixture was washed with 1N aqueous hydrochloric acid (500 mL), water (500 mL) and then brine (500 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered and then concentrated under vacuum. The residue was mixed with ethanol (about 5:1 v/w ethanol to residue) and the mixture was heated until all solid material dissolved. This solution was allowed to slowly cool to room temperature and the resulting precipitate was isolated by filtration to afford 4-{3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionylamino}-2,5-dimethylbenzoic acid methyl ester (47.3 g, 97% purity, 92% yield). m/z: [M+H+] calcd for C31H35N3O5 530.63; found 530.4.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Na].C[CH2:6][CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8](OC)=[O:9].[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1>C(O)(=O)C>[CH2:1]([O:3][C:8](=[O:9])[C:7]([CH3:6])([CH:19]1[CH2:20][CH2:21][CH2:22][C:17](=[O:23])[CH2:18]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:2]
Reactant: CCOC(=O)C(CC)C(=O)OC
Reactant: O=C1C=CCCC1
Reactant: CCO
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C(=O)OCC)C1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 2 l. 3-neck flask equipped with stirrer, condenser, thermometer, dropping funnel, and under a nitrogen atmosphere is placed 325 ml. of ethanol, and 2.5 g. of freshly cut sodium is added. When solution of the sodium is effected, 200 g. of diethyl methyl malonate is added in 5 minutes, and the mixture is stirred at room temperature for 1 hour. At the end of this period a solution of 100 g. of 2-cyclohexen-1-one in 130 ml. of ethanol is added through the dropping funnel over a period of 1 hour. The ensuing mild exothermic reaction causes the temperature to rise to 42°. Stirring is continued overnight at room temperature, after which 20 ml. of acetic acid is added, and the mixture is evaporated at reduced pressure. The residual oil is dissolved in 1.31 l. of ether, transferred to a separatory funnel and washed with three 230 ml. portions of water. The ether solution is dried over anhydrous sodium sulfate, filtered, and dried over anhydrous calcium sulfate. The ether is removed at reduced pressure and the residual oil distilled under high vacuum using a 6-inch Vigreux column. After removal of a forerun of 22.5 g., bp 49°-129°/0.14-0.21 mm, α-methyl-3-oxocyclohexane malonic acid diethyl ester distills at 129°-130°/0.2 mm; 211.5 g, 75.4% of theory.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:6]([C:11]2[CH:12]=[C:13]([Cl:19])[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)[C:7](=[O:10])[C:8]=1O)(=O)[CH3:2].[NH:27]([C:29]1[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=1)[NH2:28].S(=O)(=O)(O)N.CC(O)=O>CCO>[Cl:19][C:13]1[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=[C:11]([N:6]2[CH:5]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:4]3[C:1]([CH3:2])=[N:28][N:27]([C:29]4[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=4)[C:8]=3[C:7]2=[O:10])[CH:12]=1
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(Cl)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Reactant: COc1ncccc1NN
Agent: NS(=O)(=O)O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ncccc1-n1nc(C)c2c1C(=O)N(c1cc(Cl)c(=O)n(C)c1)C2c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
To a stirred solution of 5-(3-acetyl-2-(4-chlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-chloro-1-methylpyridin-2(1H)-one (Step 57.1) (250 mg, 0.636 mmol) and TEA (0.115 ml, 0.827 mmol) in EtOH (2 ml) was added 3-hydrazinyl-2-methoxypyridine (Step 71.1) (115 mg, 0.827 mmol) and the reaction mixture was stirred 1 hr at 90° C. Sulfamic acid (93 mg, 0.954 mmol) and AcOH (2 ml) was added and the reaction mixture was stirred 3 hr at 115° C. The reaction mixture was concentrated under reduced pressure, quenched with a saturated aq. NaHCO3 solution and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with EtOAC. The residue was further purified by SFC (column Propyl-pyridyl-urea, gradient 13-18% in 6 min_total 11 min) and triturated in hexane/Et2O (2:1) to afford the title product (13 mg, 0.026 mmol, 4% yield) as white solid. tR: 4.55 min (HPLC 1); tR: 1.04 min (LC-MS 2); ESI-MS: 496 [M+H]+ (LC-MS 2); Rf=0.41 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.02 (s, 3H) 3.43 (s, 3H) 3.89 (s, 3H) 6.24 (s, 1H) 7.15-7.22 (m, 1H) 7.32-7.37 (m, 2H) 7.40-7.45 (m, 2H) 7.88-7.96 (m, 3H) 8.28-8.33 (m, 1H).
Reaction SMILES: O[C:2]1[C:3]([O:9][S:10]([C:13]2[CH:19]=[CH:18][C:16](C)=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:4]([I:8])[CH:5]=[CH:6][CH:7]=1.[CH2:20]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(#N)C.C(O)(=O)C>[C:19]1([CH3:20])[C:13]([S:10]([O-:9])(=[O:11])=[O:12])=[CH:14][CH:15]=[CH:16][CH:18]=1.[CH2:20]([O:28][C:29]1[CH:30]=[CH:31][C:32]([I+:8][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)=[CH:33][CH:34]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH2:20]([O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Agent: CCCCCCCCOc1ccccc1
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCCCCCCOc1ccc([I+]c2ccccc2)cc1
Product: Cc1ccccc1S(=O)(=O)[O-]

Procedure:
A sample of (4-octyloxyphenyl)phenyl iodonium toluenesulfonate (in short C8-O-iodonium) was prepared according to the method of Crivello et al (J. Polym. Sci: Part A: Polymer Chemistry, (1989), 27, 3951-3968) by reacting hydroxytosyloxyiodobenzene with octyloxybenzene in a mixture of acetonitrile and acetic acid. Octyloxybenzene was previously obtained by reacting sodium phenate with bromooctane in a water/toluene mixture by phase transfer catalysis in the presence of tetrabutyl ammonium bromide. To 8 g of this compound in solution in 60 ml of methylethylketone (MEK) are added 3.02 of potassium bis-fluorosulfonylimide. The mixture is stirred magnetically for 1 hour at room temperature and filtrated to remove the insoluble potassium toluenesulfonate. The solution is poured into a flask which is adjusted to be adapted on a rotary evaporator and the solvent is evaporated. The last traces of MEK are eliminated under a vacuum primary pump and the residue is in the form of a viscous oil (8.04 g, 98%). There is added thereto an equal weight of dichloromethane enabling to give a fluid mixture which can be handled. Solubility tests are made in adjusted flasks after adding a given quantity of mixture and evaporation of the volatile fraction (CH2Cl2). Results of the tests are given below:
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[C:25]([OH:31])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:26]1/[C:25]([OH:31])=[CH:24][C:23](=[NH:22])[C:28]([O:29][CH3:30])=[CH:27]/1
Reactant: Nc1c(N)n2n(c1=O)CCC2
Reactant: COc1ccc(O)cc1N
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: COC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(O)=CC1=N

Procedure:
0.05 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 3-amino-4-methoxyphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])[CH2:17][CH2:16]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:40]([O:42][CH2:43][CH2:44]Cl)[CH3:41].N12CCCN=C1CCCCC2>C(#N)C.C(OCC)(=O)C>[CH3:1][N:2]([CH2:11][CH:12]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]([C:23]2[N:24]([CH2:41][CH2:40][O:42][CH2:43][CH3:44])[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[O:22])[CH2:17][CH2:16]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOCCCl
Reactant: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3[nH]2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOCCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3ccccc3)c3ccc(Cl)c(Cl)c3)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)-benzamide (1.36 mmol), 2-chloroethyl ethyl ether (0.59 g, 5.44 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.66 g, 10.9 mmol) in acetonitrile (16 mL). Heat to reflux. After 18 hours, cool to ambient temperature and dilute the reaction mixture with ethyl acetate. Extract twice with saturated aqueous solution of ammonium chloride, 5% aqueous solution of sodium bicarbonate, water, and saturated aqueous solution of sodium chloride. Dry the organic layer over Na2SO4, filter, and concentrate invacuo to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[C:10]([C:12](N(OC)C)=[O:13])[N:11]=1)=[O:5].C[Mg+].[Br-].O.[CH2:37]1COC[CH2:38]1>>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=2)=[C:10]([C:12](=[O:13])[CH2:37][CH3:38])[N:11]=1)=[O:5]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: C[Mg+]
Agent: [Br-]
Solvent: O
Product: CCC(=O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
To the solution of Compound 93 (220 mg, 0.47 mmol) in 10 mL of anhydrous THF was added MeMgBr (3.0 M in Et2O, 0.5 mL) at −78° C. The solution was slowly warmed to room temperature over 2 hours. The reaction mixture was treated with 10 mL of water. The mixture was extracted with Et2O, the combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (eluted with 10-100% ethyl acetate in hexanes) to give Compound 94 (184 mg, 83%) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16](=[O:30])[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](Br)=[CH:21][CH:20]=1)=[O:18].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][O:15][C:16](=[O:30])[C:17]([C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([NH:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]=2)=[CH:21][CH:20]=1)=[O:18]
Reactant: COC(=O)C(=O)c1ccc(Br)c2ccccc12
Reactant: Nc1ccnc(N2CCOCC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(=O)c1ccc(Nc2ccnc(N3CCOCC3)n2)c2ccccc12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
2-Morpholin-4-yl-pyrimidin-4-ylamine (140 mg, 0.77 mmol) and (4-bromo-naphthalen-1-yl)-oxo-acetic acid methyl ester (18) (228 mg, 0.77 mmol) were suspended in 5 mL toluene and Pd(OAc)2 (5 mg, 3 mol %), BINAP (24 mg, 5 mol5) and CS2CO3 (753 mg, 2031 mmol) were added. The reaction mixture was stirred at 100° C. for 24hrs. The cooled mixture was purified by column chromatography (0-100% EtOAc/Hex) to yield 169 mg of target product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=O.C(=O)([O-])[O-].[K+].[K+].[CH:18]([CH:20]=[CH2:21])=[O:19]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:21][C:20]([CH:18]=[O:19])=[CH:8][C:7]=2[CH:10]=1
Reactant: C=CC=O
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C=C(C=O)CO2
Temperature: 100 °C

Procedure:
The starting material is prepared as follows: 5-Methoxy-2-hydroxybenzaldehyde (25 g, 0.16 mol) and potassium carbonate (22.7 g, 0.16 mol) are taken up in 300 ml of 1,4-dioxane and treated with acrolein (13.8 g, 0.25 mol). The mixture is heated at 100° C. for 1 hour, and allowed to cool. The mixture is diluted with water and extracted three times with ether. The combined ether extracts are dried (MgSO4) and evaporated. The residual oil is dissolved in a minimal amount of ethyl acetate (approx. 40 ml) and passed through 40 g of silica gel. The gel is successively washed with several portions of a hexane/ether mixture (3:1) until no further fluorescent material is eluted. The organic phase is evaporated and the residue is crystallized from ethyl acetate/hexane to give 6-methoxy-2H-1-benzopyran-3-carboxaldehyde as a yellow solid, m.p. 49°-50° C.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C.CC(C)=O>[ClH:33].[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[C:16](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:15]/[O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(\c2ccccc2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1ccccc1/C(=C/OCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
E-(R)-1-[2-[[2-(2-Methylphenyl)-2-phenylethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (1.1 g, 0.0028 mol) (prepared as described in Method A) was dissolved in ethanol (5 ml) and 12N sodium hydroxide solution (0.7 ml) was introduced. After stirring the solution at room temperature for 2 h, 37% hydrochloric acid solution (ca. 1.0 ml) was added (with cooling) followed by dichloromethane (300 ml) and the mixture was dried (Na2SO4). Filtration and evaporation of the filtrate gave a residue, which was co-evaporated with acetone. The solid product was triturated with ethyl acetate, collected by filtration and dried in vacuo to provide the title compound (0.70 g, 62%), m.p. 195-196.
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][C:6](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Ce+3].[Cl-].[Cl-]>C(O)C>[NH:13]([C:7]1[C:6](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:10]=2[C:9](=[O:11])[CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C=CC(=O)c2ncccc21
Reactant: Nc1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCO
Product: O=C1C(Nc2ccccc2)=CC(=O)c2ncccc21
Temperature: 25 °C

Procedure:
Twenty and one-half grams of quinoline-5,8-quinone were dissolved in 500 ml of absolute ethanol, then 13 g of aniline were added, followed by the addition of 32 g of cerium chloride. This reaction mixture was refluxed overnight. The resulting mixture had a brown-blue color and was stirred and then left to cool to room temperature for about 26 hours.