Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:23][N:24]([CH:34]([C:38]1[N:47]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46](=[O:55])[C:45]2[C:40](=[CH:41][C:42]([Cl:56])=[CH:43][CH:44]=2)[N:39]=1)[CH:35]([CH3:37])[CH3:36])[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=O)[CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:23][N:24]([C@@H:34]([C:38]2[N:47]([CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:46](=[O:55])[C:45]3[C:40](=[CH:41][C:42]([Cl:56])=[CH:43][CH:44]=3)[N:39]=2)[CH:35]([CH3:37])[CH3:36])[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[N:7]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)N(CC(CCCNC(=O)OCc2ccccc2)NC(=O)OC(C)(C)C)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C2=N[C@@H](CCCNC(=O)OCc3ccccc3)CN2[C@@H](c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 240 h
Yield: 32.4 %

Procedure:
A solution of (1-{[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-(1-p-tolyl-methanoyl)-amino]-methyl}-4-benzyloxycarbonylamino-butyl)-carbamic acid tert-butyl ester (235 mg, 0.37 mmol) in CH2Cl2/TFA (4:1, 5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with CH2Cl2 and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was diluted with THF (10 mL) and saturated aqueous NaHCO3 (1 mL). The mixture was stirred at room temperature for 10 days, diluted with ether (20 mL) and washed with brine. The aqueous layer was extracted with two 10 mL portions of EtOAc and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (19:1 CH2Cl2:MeOH) to provide 81 mg (40%) of the title compound as a pale white powder. MS(ES+) m/e 675.6 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([OH:20])=O)=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.CN(C)C=O.C(Cl)(=O)CC([Cl:30])=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]([Cl:30])=[O:20])=[N:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: Cn1nc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: O=C(Cl)CC(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nc(C(=O)Cl)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (939 mg, 2.413 mmol) in dichloromethane (60 mL) in the presence of dimethylformamide (8.0 mL) was cooled to 0° C. Malonyl chloride (1.26 mL, 14.48 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was evaporated and partitioned between ethyl acetate and 1M aqueous ammonium chloride. The aqueous layer was extracted 1× with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 4-(2-fluoro-4-iodophenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carbonyl chloride. This crude material was taken into the next step without further purification. MS (EI) for C12H8N3O2ClFI: 408 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=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.C(O)C.C1(C)C=CC=CC=1>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
Under an inert atmosphere was added 3-nitrobenzene boronic acid (6.3 mmol) and sodium carbonate (11.6 mmol) to water (8 mL), toluene (8 mL) and ethanol (8 mL) and stirred for 5 minutes. p-Bromotoluene (5.8 mmol) and tetrakis(triphenylphosphine)palladium (0.3 mmol) added and heated to 70° C. for 7 hours. Concentrated under reduced pressure and extracted into chloroform (3×20 mL). The organics were then washed with 10% sodium bicarbonate (10 mL), water (10 mL) and brine (10 mL) before drying over sodium sulfate, filtering and evaporating to dryness. The residue was then purified by column chromatography and taken onto the next stage.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2.[Br:17]Br>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]([Br:17])=[C:6]2[C:11]=1[N:10]([CH3:12])[CH2:9][CH2:8][CH2:7]2
Reactant: COC(=O)c1ccc2c(c1N)N(C)CCC2
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c2c(c1N)N(C)CCC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 8-amino-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (1.05 g, 4.77 mmol) in CH2Cl2 (19 mL) at 0° C. was added Br2 (1.0 M in CH2Cl2, 4.77 mL, 4.77 mmol). The mixture was warmed slowly to rt and stirred at rt for 20 min. The resulting solution was quenched with 10% aqueous Na2S2O3 (1 mL), basified with 10% aqueous Na2CO3, and extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated to afford methyl 8-amino-5-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-7-carboxylate in pure form.
Reaction SMILES: [OH-:1].[K+].Cl.[NH2:4]O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[C:22]4[C:26](=[CH:27][C:18]=3[N:17]=2)[C:25]([CH3:29])([CH3:28])[C:24](=O)[C:23]4([CH3:32])[CH3:31])[C:9]=1[CH3:33]>CO>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:27]=[C:26]4[C:22](=[CH:21][C:19]=3[N:20]=2)[C:23]([CH3:31])([CH3:32])[C:24](=[N:4][OH:1])[C:25]4([CH3:28])[CH3:29])[C:9]=1[CH3:33]
Reactant: [OH-]
Reactant: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C
Reactant: NO
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=NO)C4(C)C)c1C
Reaction time: 0.5 h

Procedure:
A solution of 560 mg of potassium hydroxide in 1.4 ml of methanol and a solution of 700 mg of hydroxylamine hydrochloride in 3.6 ml of methanol were mixed together at 40°, whereupon the mixture was stirred for 30 minutes and 300 mg of 5,7-dihydro-2[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one were added thereto. The reaction mixture was stirred at 40° under argon for 3 days and then concentrated and treated with methylene chloride/water. The methylene chloride solution was separated, dried, filtered and evaporated. The residue was chromatographed twice on silica gel with methylene chloride/methanol (9:1), the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. 5,7-Dihydro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethyl indeno[5,6-d]imidazol-6(1H)-one oxime was obtained. After recrystallization from ethyl acetate the product melts at 160° with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])Nc1cc(Cl)nc(Cl)c1

Procedure:
A solution of 2,6-dichloropyridin-4-amine (500 g, 3.08 mol) in sulfuric acid (5 L) was cooled to 0° C. Nitric acid (2 L, 15 mol) was slowly added dropwise to the above resulting solution. The starting 2,6-dichloropyridin-4-amine was consumed after 3 hr. The reaction mixture was added to water (20 L), and the solid was filtered to give N-(2,6-dichloropyridin-4-yl)nitramide. This material was used directly in the next step. 1H NMR (CDCl3, 400 MHz): δ 7.11-7.14 (m, 1H), 7.09-7.09 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[CH2:13][C@H:12]1[C@@H:7]2[CH2:8][NH:9][CH2:10][CH2:11]1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].CCN(CC)CC>C(Cl)Cl>[CH3:16][N:9]1[CH2:8][C@H:7]2[C@H:12]([CH2:13][C:14]3[C:6]2=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH2:11][CH2:10]1.[CH2:19]([O:18][C:16]([N:9]1[CH2:8][C@H:7]2[C@H:12]([CH2:13][C:14]3[C:6]2=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH2:11][CH2:10]1)=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Cc1cccc2c1C[C@@H]1CCNC[C@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CC[C@H]2Cc3c(C)cccc3[C@H]2C1
Product: Cc1cccc2c1C[C@@H]1CCN(C)C[C@H]21

Procedure:
The title compound (9.0 mg, 0.044 mmol) was prepared by following the procedure of example 17. cis-8-Methyl-2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorene (16 mg, 0.085 mmol) was reacted with ethyl chloroformate (18.5 mg, 0.17 mmol) and Et3N (43 mg, 0.43 mmol) in CH2Cl2 (0.5 mL) to give cis-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid ethyl ester (12 mg, 0.046 mmol) which was reduced with LiAlH4 (3.5 mg, 0.093 mmol) in THF (1 mL): MS (ES) 202.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31]([O-:33])=[O:32].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CBr)cc3)c2CC1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(CS(C)(=O)=O)cc3)c2CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the crude 3-tert-butoxycarbonyl-6-(4-bromomethyl-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine in anhydrous DMF (1 mL) under nitrogen, add with string sodium methanesulfinate (400 mg, 3.9 mmol), and continue stirring for 30 min at ambient temperature followed by 2 h at 40° C. Add water, extract three times with EtOAc, wash with brine, dry over anhydrous MgSO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (3:1) to give a clear oil that solidifies on standing to a white solid (118 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][O:9]2)=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[CH:16]([C:19]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][CH2:30][NH2:31])=[CH:25][CH:26]=2)[NH:21][N:20]=1)([CH3:18])[CH3:17].CC(O)C.C(C1C2C(=CC(OCCN)=CC=2)NN=1)(C)C>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:9])[CH2:10][NH:31][CH2:30][CH2:29][O:28][C:24]2[CH:23]=[C:22]3[C:27]([C:19]([CH:16]([CH3:18])[CH3:17])=[N:20][NH:21]3)=[CH:26][CH:25]=2)=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].[ClH:1]
Reactant: CC(C)c1n[nH]c2cc(OCCN)ccc12
Reactant: CS(=O)(=O)Nc1cc([C@@H]2CO2)ccc1Cl
Solvent: CC(C)O
Product: CC(C)c1n[nH]c2cc(OCCNC[C@H](O)c3ccc(Cl)c(NS(C)(=O)=O)c3)ccc12
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Propanol (1.5 mL) was added to (R)-N-(2-chloro-5-(oxiran-2-yl)phenyl)methanesulfonamide (28.6 mg) that can be produced by the method described in Reference Example 69 or the like, and a 2-(3-isopropylindazol-6-yloxy)ethanamine-2-propanol solution [37.5 μL; solution prepared by dissolving 2-(3-isopropylindazol-6-yloxy)ethanamine (306.4 mg) that can be produced by the method described in Reference Example 68 or the like, in 2-propanol (347.5 μL)]. The mixture was stirred overnight at reflux. The reaction solution was cooled to room temperature, and then nitrogen gas was blown into the reaction solution to evaporate the solvent. The resulting residue was purified by HPLC, and then the purification product was dissolved in water (1 mL) and a 1 mol/L aqueous solution of hydrochloric acid (150 μL; manufactured by Kanto Chemical Co., Inc.). The solution was freeze-dried, and thus the title compound was obtained in the form of hydrochloride (18.1 mg).
Reaction SMILES: Cl.N[C:3]1CC[N:5]([C:8]2[S:9][C:10]3[CH2:16][CH2:15][CH2:14][CH2:13][C:11]=3[N:12]=2)[N:4]=1.C(NNC(N)=S)=[O:18].[Cl:24]C1CCCCC1=O>CN(C)C=O>[ClH:24].[CH:3]([NH:4][NH:5][C:8]1[S:9][C:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:11]=2[N:12]=1)=[O:18]
Reactant: NC(=S)NNC=O
Reactant: O=C1CCCCC1Cl
Reactant: NC1=NN(c2nc3c(s2)CCCC3)CC1
Agent: Cl
Solvent: CN(C)C=O
Product: O=CNNc1nc2c(s1)CCCC2
Reaction time: 3 h

Procedure:
The 2-hydrazino-4,5,6,7-tetrahydro-benzothiazole hydrochloride used above is prepared in accordance with the method of Y.Usui [CA 70,96685 (1969)] via Hantzsch synthesis, with better yields by modification of the conditions. A mixture of 20 g of formylthiosemicarbazide, 22.3 g of 2-chlorocyclohexanone and 150 ml of dimethylformamide is kept at 70°-80° C. for 3 hours. On cooling, some of the product crystallises out. The dimethylformamide is distilled off in vacuo and the residue is recrystallised from ethanol. 27.4 g of 1-formyl-2-(4,5,6,7-tetrahydro-benzothiazolyl)-hydrazine hydrochloride of melting point 171°-173° C. are obtained.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=O.[CH2:9]([O:11][CH2:12]CBr)[CH3:10].COCCN1CCNCC1>>[CH2:9]([O:11][CH2:12][CH2:1][N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:10]
Reactant: O=CN1CCNCC1
Reactant: CCOCCBr
Agent: COCCN1CCNCC1
Product: CCOCCN1CCNCC1

Procedure:
The title compound was prepared from formylpiperazine and 2-bromoethyl ethyl ether in the same manner as in Preparation Example 1(5) to (7). 1H NMR(CDCl3, δ ppm): 1.19(3H, t), 2.46-2.49(2H, m), 2.55-2.61(4H, m), 2.88-2.92(4H, m), 3.45-3.59(4H, m)
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:8]=2[CH2:9][NH:10]C(=O)OC(C)(C)C)=[O:6])[CH2:3][CH2:2]1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>C(Cl)Cl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[NH2:10][CH2:9][C:8]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:7]=1[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:6]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1C(=O)NC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(F)cc1C(=O)NC1CC1
Yield: 100 %

Procedure:
A solution of tert-butyl 2-(cyclopropylcarbamoyl)-4-fluorobenzylcarbamate (130 mg, 0.42 mmol), prepared according to literature methods, in CH2Cl2 (5 mL) was stirred with trifluoroacetic acid (3 mL) at room temperature for 10 min, then concentrated in vacuo to give 140 mg (Yield 100%) of the title compound as a foam: 1H NMR (DMSO-d6, 300 MHz) δ ppm: 0.62 (2H, m, CH2), 0.73 (2H, m, CH2), 2.86 (1H, m, CH), 4.02-4.07 (2H, ABq, NCH2), 7.46 (2H, m, Ar—Hs), 7.58 (1H, m, Ar—H), 8.11 (3H, br, NH3), 8.81 (1H, d, J=4.4 Hz, NH); LC/MS m/z 209 (M+H).
Reaction SMILES: [Ce].[N+]([O-])(O)=O.[N+]([O-])([O-])=[O:7].[NH4+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]=[O:7])=[CH:13][CH:14]=1
Reactant: COc1ccc(C)cc1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O=[N+]([O-])O
Product: COc1ccc(C=O)cc1
Yield: 96 %

Procedure:
The same procedure as in Example 1 is repeated except that the cerium salt is electrolyzed with 10 ml of 65% by weight aqueous solution of nitric acid placed into the cathode chamber in place of ammonium nitrate. p-Methyl anisole is oxidized with the solution withdrawn from the anode chamber to give anisaldehyde in a yield of 96.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15](OCC)=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][C:3]=1[F:21].C(N(C(C)C)C(C)C)C.Cl.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][C:3]=1[F:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(F)c(Cl)cc2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)c(Cl)cc2C(C)(C)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
Ethyl 7-chloro-6-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (820 mg, 2622 μmol) was dissolved in 1,4-dioxane (5244 μL) and N-ethyl-N-isopropylpropan-2-amine (1370 μL, 7866 μmol). tert-Butyl 2-aminoacetate hydrochloride (659 mg, 3933 μmol) was added, and the reaction was stirred at 80° C. for 3 hours. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (200 mg) as a white solid after flash chromatography. MS m/e 420 (M+Na)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[CH3:17])=[CH:29][CH:28]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: CC1CCCN1Cc1ccc(N)cc1
Solvent: CN(C)C=O
Product: CC1CCCN1Cc1ccc(N/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 14.5 %

Procedure:
To a solution of 0.2 g (0.61 mmol) of (4E)-6-iodo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione in 2 mL of N,N′-dimethylformamide is added {4-[(2-methylpyrrolidin-1-yl)methyl]phenyl}amine (0.14 mL, 0.73 mmol). The reaction mixture is heated at 100° C. under N2. Mass spectroscopy suggested the completion of reaction after 45 min. The reaction mixture is concentrated under high-pressure vacuum. Purification is performed by silica gel chromatography using 5% MeOH/CHCl3 as solvent. Concentrating the organic layer containing product afforded 0.043 g (14.5% yield) of yellow solid: mp 157-158° C.; MS (ESI) m/z 488.4 (M+H)+1
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=1[NH2:16]>>[F:13][C:14]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1
Reactant: COc1ccc(N)c(F)c1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: COc1ccc(Nc2nc(C)nc3ccccc23)c(F)c1

Procedure:
The title compound was prepared from 4-chloro-2-methylquinazoline and 2-fluoro-4-methoxyaniline by a procedure similar to example 28 (79%). 1H NMR (CDCl3): 8.54 (m, 1H), 7.83 (m, 2H), 7.65 (m, 1H), 7.50 (m, 1H), 7.47 (s, broad, 1H), 6.74-6.81 (m, 2H), 3.83 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:19]=[CH:18][C:17]([CH2:16][N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[CH:22][CH:21]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(CN3Cc4cccn4Cc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 109.9 %

Procedure:
A mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.200 g, 1.09 mmol), 4-bromomethyl-biphenyl (0.322 g, 1.303 mmol) and potassium carbonate (0.300 g, 2.17 mol) in dry N, N-dimethyl formamide (6 mL) was stirred at room temperature under nitrogen for 24 hours. The reaction mixture was then partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The separated organic phase was washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a colorless syrup (0.42 g). Purification by flash chromatography using a solvent gradient of 0 to 5% ethyl acetate in hexane afforded a white foam that was crystallized from ethyl acetate/hexane to afford the title compound (0.261 g, 68%) as a white crystalline solid, m.p. 135-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1Cl.C1CCN2C(=NCCC2)CC1>CN1C(=O)CCC1>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Oc1cc(F)ccc1Cl
Reactant: Clc1ccncc1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Product: Fc1ccc(Cl)c(Oc2ccncc2Br)c1
Yield: 84 %

Procedure:
A mixture of 2-chloro-5-fluorophenol (1.50 g, 10.24 mmol), 3-bromo-4-chloropyridine (1.50 g, 7.79 mmol) and DBU (1.50 g, 9.85 mmol) were heated at 130° C. in NMP (10 mL) for 15 hours. The reaction mixture was cooled and partitioned between water (100 mL) and MTBE (100 mL). The organic layer was separated, washed with dilute aq NaOH and brine, dried (MgSO4) and concentrated in vacuo to provide 3-bromo-4-(2-chloro-5-fluorophenoxy)pyridine (1.98 g, 84% yield) as brownish oil suitable for use in the next reaction. MS (ESI) m/z: 303.9 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#N)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)[OH:13].[OH2:17]>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:13])=[O:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCc1cc(Cl)cc(Cl)c1
Reactant: O
Solvent: CCCCCC
Product: O=C(O)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The nitrile was dded to a mixture of 10 mL of concentrated sulfuric acid and 50 mL H2O and heated to reflux for 48 hours, cooled to room temperature and stirred for 48 hours. The reaction was diluted into 1 L of crushed ice, warmed to toom temperature and extracted with 2×200 mL of dichloromethane and 2×200 mL of ethylacetate. Both sets of organics were combined and washed with saturated aqueous NaHCO3. The NaHCO3 fractions were combined and acidified to pH 1 with 3N HC1. The white solid was too fine to filter and was extracted out with 2×200 mL of dichloromethane. The combined organics were dried with Na2SO4 and the solvents removed at reduced presure to yield crude 3,5dichlorophenylacetic acid as a white solid. The solid was slurried with hexane and filtered to get 1.75g of white solid.
Reaction SMILES: Br[C:2]1([CH3:10])[CH:7]=[CH:6][C:5](Br)([CH3:8])[CH:4]=[CH:3]1.[C:11]([Cu])#[N:12].[CH3:14][N:15](C=O)C>>[C:14]([C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([C:11]#[N:12])([CH3:8])[CH:4]=[CH:3]1)#[N:15]
Reactant: CN(C)C=O
Reactant: N#C[Cu]
Reactant: CC1(Br)C=CC(C)(Br)C=C1
Product: CC1(C#N)C=CC(C)(C#N)C=C1
Temperature: 50 °C
Yield: 77 %

Procedure:
A mixture of 1,4-dibromo-p-xylene (52.8 g, 0.2 mole), CuCN (53.4 g, 0.6 mole), and DMF (150 mL) is refluxed for about 19 hours. The yellow crystals formed are isolated by pouring the slurry into water and filtration. The crude product is stirred with a mixture of 500 mL of water and 100 mL of ethylenediamine until the yellow color has disappeared. The grey crystalline solid is added to a solution containing 200 mL of water, 50 mL of conc. HCl, and 50 g of ferric chloride hexahydrate and the resulting slurry stirred is warmed to about 50° C. for 30 minutes. The off-white crystalline solid is collected by filtration and recrystallized from 1.8 L of ethanol, yielding 24.0 g (77 percent yield) of 1,4-dicyano-p-xylene.