Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].FC(F)(F)S(O[C:8]1[C:13]([Br:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[C:16](=[O:18])[CH3:17])(=O)=O.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1>O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:14][C:13]1[C:8]([C:24]2[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=2)=[C:9]([C:16](=[O:18])[CH3:17])[CH:10]=[C:11]([Cl:15])[CH:12]=1
Reactant: CC(=O)c1cc(Cl)cc(Br)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cc(Cl)cc(Br)c1-c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 89.2 %

Procedure:
A solution of sodium hydrogenecarbonate (2.0 g, 23 mmol) in water (50 mL) was treated with a solution of 2-acetyl-6-bromo-4-chlorophenyl trifluoromethanesulfonate (4.5 g, 12 mmol) in toluene (50 mL) followed by (3,5-difluorophenyl)boronic acid (2.0 g, 13 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.67 g, 0.58 mmol). The reaction mixture was degassed with nitrogen for 5 min and heated at 80° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with sodium bicarbonate, water, and brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0%-10%) gave the desired product (3.7 g, 82%). LCMS for C14H9BrClF2O (M+H)+: m/z=344.9, 346.9. Found: 344.9, 346.8.
Reaction SMILES: [ClH:1].[CH3:2][C@H:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:4]1[NH:12]C(=O)COC>C(O)C.O>[ClH:1].[NH2:12][C@H:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][C@@H:3]1[CH3:2]
Reactant: COCC(=O)N[C@H]1c2ccccc2C[C@@H]1C
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@H]1Cc2ccccc2[C@@H]1N

Procedure:
Concentrated hydrochloric acid (8 ml) was added to a solution of N-[(1R,2S)-2-methyl-1-indanyl]-2-methoxyacetamide (5.9 g, 0.0269 mol) in ethanol and water, and the mixture heated for 12 hours at reflux. The solvent was evaporated and a small amount of ethyl acetate added. The undissolved solid was filtered off to give (1R,2S)-1-amino-2-methylindane hydrochloride (1.0 g) as a solid, chemical purity>95%.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.C([NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:30])=[O:29])(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:40][C:37]([F:38])([F:39])[C:34]1[CH:33]=[CH:32][C:31]([S:28]([NH2:27])(=[O:29])=[O:30])=[C:36]([C:2]2[CH:22]=[CH:21][C:5]3[NH:6][C:7]([CH2:9][O:10][C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=4)=[N:8][C:4]=3[CH:3]=2)[CH:35]=1
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(C(F)(F)F)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: NS(=O)(=O)c1ccc(C(F)(F)F)cc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.100 g, 0.269 mmol, from Example 1.1), N-tert-butyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4-trifluoromethyl-benzenesulfonamide (0.165 g, 0.404 mmol), sodium carbonate (0.171 g, 1.61 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.035 g, 0.0538 mmol) in DME (2 mL) and H2O (0.5 mL) was heated at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide a residue, which was purified by chromatography (silica, hexanes:EtOAc, 1:1) to afford the product as a off-white solid. The obtained material was dissolved in TFA (2 mL) and the resulting solution was heated to 60° C. for 3 hours. The reaction mixture was concentrated in vacuo to provide a residue which was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the title compound as a brown solid (0.101 g, 73%). 1H NMR (400 MHz, CD3OD) δ (ppm): 0.33 (d, 1H, J=8.0 Hz), 7.89 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.82 (d, 1H, J=0.8 Hz), 7.76 (d, 1H, J=8.8 Hz), 7.69-7.65 (m, 3H), 7.50 (dd, 1H, J=8.8 Hz, J=1.6 Hz), 7.28 (d, 2H, J=8.8 Hz), 5.62 (s, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H16F6N3O3S: 516.4 (M+H), Found 516.3.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[N+](=[CH2:15])=[N-].S([O-])([O-])(=O)=O.[Mg+2]>CO.C(OCC)C>[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:15])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1cccc2[nH]ccc12
Yield: 98 %

Procedure:
To a solution of indole-4-carboxylic acid (506 mg, 3.14 mmol) dissolved in a mixture of methanol (5 mL) and diethyl ether (10 mL) was added ethereal diazomethane until disappearance of starting acid was indicated by TLC. Anhydrous magnesium sulfate was then added and the solution filtered and concentrated in vacuo. Flash chromatography on 10 g of Merck silica gel eluted with 2:1, chloroform:hexanes, followed by 10:1, chloroform:diethyl ether afforded the title compound (540 mg, 98%).
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].Cl>CS(C)=O.CCOC(C)=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])[C:3]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C(=O)OC)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a mixture of NaH (60%, 7 g, 0.16 mol) in dimethyl sulfoxide (150 mL) was added dropwise dimethyl malonate (20 mL, 0.16 mol). The mixture was heated to 100° C. for 10 min then cooled to room temperature, followed by the addition of 2,5-difluoronitrobenzene (14 g, 0.08 mol). After stirred at 90° C. for 2 h, the mixture was cooled and poured into 5% aq.HCl with ice cooling. EtOAc (50 mL) was added and the organic phase was separated, washed by water and dried with Na2SO4. The solvent was removed in vacuo to give 2-(4-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (19.4 g). 2-(4-fluoro-2-nitro-phenyl)-malonic acid dimethyl ester (6 g, 22 mmol) was dissolved in glacial acetic acid (30 mL), the aqueous HCl (6N, 30 mL) was added and the reaction mixture were heated ar refluxing for 4 h, Iron power (5 g, 88 mmol) was added portionwise to the mixture and the refluxing was allowed to continue for another 2 h. The solvent was removed in vacuo and the remaining residue was extracted by EtOAc. The organic phase washed with aqueous HCl (1N), brine and dried over Na2SO4. concentrated to give the titled compound as a yellow solid (3 g, 89%).
Reaction SMILES: [CH3:1][O:2]C1C=CC=C2C=1NC=C2C=O.[C:14]([C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](Cl)[CH:24]=2)[N:19]([CH2:27][C:28]([OH:30])=[O:29])[CH:18]=1)(=[O:16])[NH2:15]>>[C:14]([C:17]1[C:25]2[C:20](=[C:21]([O:2][CH3:1])[CH:22]=[CH:23][CH:24]=2)[N:19]([CH2:27][C:28]([OH:30])=[O:29])[CH:18]=1)(=[O:16])[NH2:15]
Reactant: COc1cccc2c(C=O)c[nH]c12
Reactant: NC(=O)c1cn(CC(=O)O)c2ccc(Cl)cc12
Product: COc1cccc2c(C(N)=O)cn(CC(=O)O)c12

Procedure:
was prepared from 7-methoxy-1H-indole-3-carbaldehyde [109021-59-2] in a similar manner as described in Scheme A11 for the preparation of (3-carbamoyl-5-chloro-indol-1-yl)-acetic acid. White solid. MS (LC/MS): 249 [M+H]+, 497 [2M+H]+; tR (HPLC conditions c): 3.05 min.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:3]=1[O:4][CH2:5][C:6](=O)[CH3:7].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][NH2:33])=[N:26][CH:27]=1.[Cl-].[NH+]1C=CC=CC=1.Cl>N1C=CC=CC=1>[F:34][C:21]([F:20])([F:35])[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][N:33]=[C:6]([CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:12][C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:10][C:9]=2[Cl:19])[CH3:7])=[N:26][CH:27]=1
Reactant: CC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: NOCCCOc1ccc(C(F)(F)F)cn1
Agent: Cl
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: CC(COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A mixture of 0.34 g of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)-phenoxy)acetone, 0.24 g of O-(3-(5-trifluoromethyl-2-pyridyloxy)propyl)-hydroxylamine, 0.14 g of pyridinium chloride, and 10 ml of pyridine was stirred at room temperature for 2 hours. The reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.40 g (yield, 71%) of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-acetone O-(3-(5-trifluoromethyl-2-pyridyloxy)propyl)oxime, nD23.0 1.5310.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.Br[C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:33][C:27]([O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:25][CH:24]=3)=[CH:12][CH:13]=2)=[CH:18][CH:19]=1)([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: Cc1ccc(C(=O)NCCc2ccc(-c3ccc(O)cc3)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccc(C)cc3)cc2)cc1
Yield: 17 %

Procedure:
Ethyl 2-Methyl-2-{4[2-(4-methyl-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(4-methyl-benzamido)-ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 1. Yield 17% of theory; m.p. 214° C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]5[C:30]6[C:25](=[C:26]([O:39][CH3:40])[C:27]([O:31][CH2:32]C7C=CC=CC=7)=[CH:28][CH:29]=6)[N:24]=[CH:23][N:22]=5)[CH2:16][C:15]=4[CH:41]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1.BrC[C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:45]=1>>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]4[O:20][CH2:19][CH2:18][N:17]([C:21]5[C:30]6[C:25](=[C:26]([O:39][CH3:40])[C:27]([O:31][CH2:32][C:44]7[CH:53]=[CH:52][C:51]8[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=8)[N:45]=7)=[CH:28][CH:29]=6)[N:24]=[CH:23][N:22]=5)[CH2:16][C:15]=4[CH:41]=3)[CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: BrCc1ccc2ccccc2n1
Reactant: COc1c(OCc2ccccc2)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12
Product: COc1c(OCc2ccc3ccccc3n2)ccc2c(N3CCOc4ccc(-c5ccc6nc(C)[nH]c6c5)cc4C3)ncnc12

Procedure:
Synthesized according to the method of example 10 using 7-(2-methyl-1H-benzimidazol-6-yl)-4-{8-(methyloxy)-7-[(phenylmethyl)oxy]quinazolin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (example 1) in step 1 and 2-bromomethylquinoline in step 2. 1H NMR (400 MHz, d6-DMSO): 8.64 (s, 1H), 8.47 (d, 1H), 8.03 (m, 4H), 7.83 (m, 4H), 7.73 (d, 1H), 7.63 (m, 3H), 7.02 (d, 1H), 5.64 (s, 2H), 5.43 (br s, 3H) 4.62 (br s, 2H), 4.51 (br s, 2H), 4.01 (s, 1H), 2.80 (s, 3H); MS (EI) for C36H30N6O3: 595 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH2:9])[CH2:4]1.[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[N:24]=[C:25]=[S:26])([CH3:14])[CH3:13].Cl>>[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25]([NH:9][CH:5]1[CH2:6][CH2:7][CH2:8][CH:3]([C:2]([F:10])([F:11])[F:1])[CH2:4]1)=[S:26])([CH3:13])[CH3:14]
Reactant: NC1CCCC(C(F)(F)F)C1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=S
Agent: Cl
Product: CC(C)c1cccc(C(C)C)c1NC(=S)NC1CCCC(C(F)(F)F)C1
Reaction time: 12 h

Procedure:
16.0 g of 3-trifluoromethyl-cyclohexylamine are taken and 18.0 g of 2,6-diisopropyl-phenyl isothiocyanate are introduced whilst stirring. The reaction commences with slight evolution of heat. The mixture is left to stand for 12 hours and is then stirred with dilute hydrochloric acid. The crystalline product is filtered off, triturated with dilute methanol, filtered off and dried. The compound is obtained in the form of a stereomer mixture of melting point 67°-75° C.; yield 27 g. The elementary analysis and NMR and IR spectra agree with the assumed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:32]([Mg]Br)[CH3:33].Cl>C1COCC1.C(OCC)(=O)C>[CH2:32]([C:11]1[N:10]=[C:9]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:16])=[C:13]([CH3:27])[N:12]=1)[CH3:33]
Reactant: Cc1nc(S(C)(=O)=O)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Reactant: CC[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 1 h

Procedure:
100 mg (0.209 mmol) of 4-(3,5-dichlorophenyl)-6-methyl-2-(methylsulfonyl)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 3 ml of THF. 0.314 ml (13% THF solution, 1 mol/l) of ethylmagnesium bromide was added at 0° C. and stirred at the same temperature for 1 hour. 10% hydrochloric acid was added at the same temperature and stirred for 10 minutes. After the reaction mixture was diluted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][C:13]([OH:15])=O.C(Cl)CCl.C[CH2:21][N:22](CC)[CH2:23]C.Cl.CNC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][C:13]([N:22]([CH3:23])[CH3:21])=[O:15]
Reactant: CCN(CC)CC
Reactant: COc1ccc([N+](=O)[O-])cc1CC(=O)O
Agent: CNC
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1CC(=O)N(C)C

Procedure:
2-(2-Methoxy-5-nitrophenyl)acetic acid (17.1 g, 1 eq, Step B), EDC (18.6 g, 1.2 eq.), Et3N (9.8 g, 13.6 mL, 1.2 eq) and dimethylamine hydrochloride (7.9 g, 1.2 eq.) in 150 mL of CH2Cl2 were stirred together with exclusion of air overnight. CH2Cl2 (150 mL) was added and the mixture was washed twice with 1M HCl, twice with 1M NaOH, water and brine. Removal of the solvent under reduced pressure followed by silica gel chromatography (90:10 CH2Cl2:EtOAc) afforded pure 2-(2-methoxy-5-nitrophenyl)-N,N-dimethyl-acetamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].Br[CH2:17][CH2:18][N:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=2)[C:20]1=[O:33]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:17][CH2:18][N:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:25]=3)[C:20]2=[O:33])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: COC(=O)c1ccc2ccn(CCBr)c(=O)c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccn(CCOc3ccc(OC)cc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-methoxyphenol (74 mg, 0.59 mmol) in THF (2.5 mL) was added potassium tert-butoxide (52 mg, 0.46 mmol). The reaction mixture was stirred at rt for 3 h, then methyl 2-(2-bromoethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (80 mg, 0.26 mmol) in DMF (2.5 mL) was added and the resulting mixture was stirred at rt overnight. The mixture was then concentrated to afford methyl 2-[2-(4-methoxyphenoxy)ethyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate. LC-MS: (FA) ES+354.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[OH:12]O>CCOCC>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: OO
Reactant: OB(O)c1cccc(F)c1F
Solvent: CCOCC
Product: Oc1cccc(F)c1F
Reaction time: 2 h

Procedure:
The boronic acid in an amount of 9.0 g was dissolved in 60 ml of an ether, and the solution thus formed was added dropwise with 60 ml of a 10% aqueous hydrogen peroxide while being refluxed under a heated condition. After the dropping of the aqueous hydrogen peroxide was finished, the reflux under a heated condition was further continued for 2 hours. Then, the ether layer was separated with a separating funnel, washed with water, dried, and then subjected to distillation under a reduced pressure to separate the solvent to obtain 7.1 g of 2,3-difluorophenol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([CH3:14])[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18][CH3:19])=[O:17])=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:9]=1>O1CCCC1>[CH3:14][C:12]1[C:11]([CH:15]([CH2:20][CH2:21][CH3:22])[C:16]([O:18][CH3:19])=[O:17])=[C:10]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:9]=[C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:13]=1
Reactant: C1COCCN1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCOCC2)nc1-c1ccc(C)cc1
Yield: 80.7 %

Procedure:
Methyl 2-(4-methyl-2-morpholino-6-p-tolylpyrimidin-5-yl)pentanoate was prepared according to the general method A starting from morpholine (0.107 mL; 1.20 mmol) and methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.100 g; 0.239 mmol) in tetrahydrofuran (2 mL). Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-25%) in heptane furnished 74 mg (81%) of the title compound as an oil. ESI/APCI(+): 384 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[C:13]3[C:18]([NH:19][C:4]=2[C:3]1=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=3.[H-].[Na+].C1COCC1.[Cl:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>Cl>[ClH:28].[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[C:13]3[C:18]([N:19]([CH2:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:4]=2[C:3]1=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=3
Reactant: ClCCCN1CCCCC1
Reactant: CN1C(=O)c2[nH]c3ccccc3c2Oc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2c(c3ccccc3n2CCCN2CCCCC2)Oc2ccccc21

Procedure:
A mixture of 1.8 g of 7-methyl-7H-indolo [3,2-b][1,5]benzoxazepin-6(5H)-one, 0.42 g of 57% sodium hydride-mineral oil dispersion and 10 ml of THF was refluxed for 15 min. and then treated with 4.0 g of 3-chloropropylpiperidine. The mixture was refluxed for 24 hrs., diluted with 2 N HCl and extracted with ether. The aqueous layer was made basic with 5% NaOH and the oil extracted with ether. The ether phase was dried and treated with dry HCl to give a white solid. The solid was recrystallized from methanol-ether to give analytical material, mp. 205°-6°.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[C:23]([O:33][CH3:34])[CH:22]=4)[CH:19]=3)[N:14]([S:35]([C:38]3[CH:44]=[CH:43][C:41]([CH3:42])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:13]=2)[CH:9]=[N:8]1.[CH3:48][C@H:49]1[CH2:51][O:50]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:48][C@@H:49]([OH:50])[CH3:51])[CH2:31][CH2:32]5)=[C:23]([O:33][CH3:34])[CH:22]=4)[CH:19]=3)[N:14]([S:35]([C:38]3[CH:39]=[CH:40][C:41]([CH3:42])=[CH:43][CH:44]=3)(=[O:36])=[O:37])[CH:13]=2)[CH:9]=[N:8]1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCNCC1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C[C@H](C)O)CC1
Yield: 68.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-methoxy-4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (100 mg. 0.148 mmol) was alkylated using (S)-2-methyloxirane (26 mg, 0.445 mmol), DIPEA (115 mg, 0.891 mmol) and ethanol (5 mL) to get crude 70 mg of the titled compound. MS: m/z=695.3 (M+1).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]O>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[O:23][CH3:22])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: COc1ccccc1CO
Product: COc1ccccc1CN1C(=O)C(CCO)Oc2ccccc21

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by methods F and G, alkylating with the methanesulfonate ester of 2-methoxybenzyl alcohol, in 47% overall yield as a light yellow gum after flash chromatography, eluting with EtOAc/hexanes, IR (Neat) 3436, 2941, 1583, 1683, 1501, 1466, 1403, 1281, 1246, 1113, 1052, 751 cm-1 ; 1H NMR (CDCl3) δ 2.18-2.36 (m, 2H), 2.39 (br t, J=6.0 Hz, 1H), 3.90 (s, 3H), 3.92 (br q, J=5.5 Hz, 2H), 4.85 (dd, J=7.4, 5.7 Hz, 1H), 5.15 (s, 2H), 6.81-7.03 (m, 7H), 7.23 (td, J=8.3, 1.7 Hz, 1H); MH+ at m/z=314; Anal. Calc'd for C18H19NO4.0.2 H2O: C, 68.21; H, 6.17; N, 4.42. Found: C, 68.36; H, 6.18; N, 4.36.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[NH2:20][C:21]1[C:22]([C:33]#[N:34])=[N:23][CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:26]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[F:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH:20][C:21]1[C:22]([C:33]#[N:34])=[N:23][CH:24]=[C:25]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:26]=1)=[C:3]([CH3:19])[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:5]2
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Reactant: N#Cc1ncc(N2CCOCC2)cc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Nc1cc(N2CCOCC2)cnc1C#N

Procedure:
Prepared according to general Procedure K using 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (93 mg, 0.34 mmol), 3-amino-5-morpholinopicolinonitrile (70 mg, 0.34 mmol) and a 4.0M solution of HCl in dioxane (0.08 mL, 0.34 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 3-((5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-5-(4-morpholinyl)-2-pyridinecarbonitrile was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.68 (1H, dt, J=3.1, 1.6 Hz), 8.00 (1H, d, J=8.6 Hz), 7.87-7.97 (3H, m), 7.64 (1H, td, J=8.2, 5.5 Hz), 7.39 (1H, ddd, J=7.0, 4.9, 1.8 Hz), 7.17-7.32 (2H, m), 6.23 (1H, d, J=2.3 Hz), 3.75-3.86 (4H, m), 3.17-3.31 (4H, m), 2.29 (3H, s). Mass Spectrum (ESI) m/e=441.1 (M+1).