Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1>>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][C:26]4[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: Cn1ccnc1CCl
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCc1nccn1C
Yield: 95.2 %

Procedure:
Using an analogous procedure to that described in Example 25, 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (224 mg, 0.7 mmol), (prepared as described for the starting material in Example 24), and 2-chloromethyl-1-methylimidazole hydrochloride (140 mg, 0.8 mmol) were combined to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline hydrochloride (150 mg, 44%).
Reaction SMILES: C(N(CC)CC)C.C(O[C@H:12]1[NH:15][C:14](=[O:16])[C@@H:13]1[C@H:17]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][O:19][SiH:20]([CH3:22])[CH3:21])(=O)C.[N+:27](=[C:29]([C:36](=[O:38])[CH3:37])[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])=[N-:28].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[C:23]([C@@H:17]([C@H:13]1[C@@H:12]([CH2:37][C:36](=[O:38])[C:29]([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])=[N+:27]=[N-:28])[NH:15][C:14]1=[O:16])[CH2:18][O:19][SiH:20]([CH3:21])[CH3:22])([CH3:24])([CH3:25])[CH3:26]
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(C)=O
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](CO[SiH](C)C)C(C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)C(=[N+]=[N-])C(=O)C[C@H]1NC(=O)[C@H]1[C@@H](CO[SiH](C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
7.2 ml (52 mmol - 2.6 equivalents) of triethylamine are added to a solution, which has been cooled to 0° C., of 5.75 g (20 mmol) of (3R,4R)-4-acetoxy-3-[(1R)-1-tert.-butyldimethylsilyloxyethyl]azetidin-2-one [S. Oida et al. Chem. Pharm. Bull. 29 2899 (1981); M. Shiozaki et al. Tetrahedron 39 2399 (1983)] and 4.37 g (26 mmol - 1.3 equivalents) of allyl 2-diazo-3-oxobutanoate in 190 ml of anhydrous dichloromethane, and then 9.3 ml (48 mmol - 2.4 equivalents) of trimethylsilyl trifluoromethanesulphonate are added dropwise. The cooling bath was removed, and the mixture was stirred at room temperature for 1 h, 1.55 ml (8 mmol - 0.4 equivalent) of trimethylsilyl trifluoromethanesulphonate were added, and the mixture was stirred for a further 0.5 h at room temperature. The reaction solution was then poured into a mixture of cold, saturated NaHCO 3 solution and ethyl acetate, and extraction with ethyl acetate was carried out, and the combined organic extracts were washed with saturated NaCl solution and dried over MgSO4. The solvent was evaporated in vacuo, and the residue was filtered through 150 g of silica gel (toluene:ethyl acetate 4:1). 6.4 g (81%) of the title compound were obtained as pale crystals, melting point: 66° C., Rf: 0.33 (toluene:ethyl acetate 7:3) [α]D20 =59.2° (c 0.969, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[NH2:12]C1C=CC=CC=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Product: Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 1-bromo-4-fluoro-3-nitrobenzene (2270 mg, 10.01 mol), aniline (3 ml) and DMF (20 ml) was heated at 100° C. under an atmosphere of Nitrogen for 7 h. The mixture was then concentrated in vacuo, and the residue triturated with heptane (30 ml) to give the desired product. 1H NMR (400 MHz, CDCl3) δ=7.11 (d, 1H, J=9.2 Hz), 7.25-7.29 (m, 3H), 7.40-7.45 (m, 3H), 8.35 (d, 1H J=2.4 Hz) and 9.45 firs, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH3:4].[CH2:10]([O:12][C:13]([C:15]1[C:16]([CH2:39]Cl)=[N:17][C:18]2[C:23]([C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)=[CH:22][C:21]([O:35][CH3:36])=[C:20]([O:37][CH3:38])[CH:19]=2)=[O:14])[CH3:11].O>CN(C)C=O>[CH2:10]([O:12][C:13]([C:15]1[C:16]([CH2:39][N:6]2[CH:7]=[CH:8][N:9]=[C:5]2[CH2:3][CH3:4])=[N:17][C:18]2[C:23]([C:24]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1)=[CH:22][C:21]([O:35][CH3:36])=[C:20]([O:37][CH3:38])[CH:19]=2)=[O:14])[CH3:11]
Reactant: CCc1ncc[nH]1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cn2ccnc2CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
Oily sodium hydride (60%, 0.323 g) was added to a solution of 2-ethylimidazole (0.776 g) in N,N-dimethylformamide (30 ml), followed by stirring at room temperature for 15 minutes. Then 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester (3.0 g) was added. After stirring at 80° C. for 1 hour, the reaction mixture was poured over water, and the separating crystal was collected by filtration, which was then recrystallized from ethanol to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-ethylimidazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (2.5 g, 74%) as a colorless prismatic crystal having a melting point of 163° to 164° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]1[CH:39]=[C:38]([C:40]2[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=2)[NH2:43])[CH:37]=[N:36]1.Cl.C([O-])(O)=O.[Na+]>C(O)C(F)(F)F.CCOC(C)=O>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[C:40]([C:38]4[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=4)[CH:41]=3)[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: Cn1cc(-c2cccc(N)c2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: OCC(F)(F)F
Product: Cn1cc(-c2cccc(Nc3nccc(-c4c(-c5cccc(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c2)cn1
Temperature: 80 °C
Yield: 63.4 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.100 g, 0.217 mmol) and 3-(1-methyl-1H-pyrazol-4-yl)aniline (0.0563 g, 0.325 mmol) was dissolved in 4 mL of trifluoroethanol with stirring. HCl (0.11 mL, 4N in dioxane, 0.44 mmol) was added, and the vessel was sealed. The reaction was heated to 80° C. for 4.5 days and cooled to rt. The reaction was poured into half-saturated aqueous NaHCO3 solution and EtOAc. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded a solid that was triturated with diethyl ether to yield 0.0823 g (63%) of the desired compound. 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.73 (s, 1H), 9.52 (d, J=5.1 Hz, 1H), 8.37-8.30 (m, 2H), 8.03 (d, J=7.3 Hz, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.83 (d, J=7.3 Hz, 1H), 7.74 (d, J=8.2 Hz, 1H), 7.69 (s, 1H), 7.59 (t, J=7.7 Hz, 1H), 7.54-7.43 (m, 2H), 7.42-7.32 (m, 1H), 7.26-7.11 (m, 4H), 7.00-6.92 (m, 1H), 6.61 (d, J=5.3 Hz, 1H), 3.80 (s, 3H). MS (M+H, ES+) 599.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[NH:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([OH:23])=O.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[NH:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([NH:42][O:41][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:23]
Reactant: COc1cccc(Nc2cc(F)c(F)cc2C(=O)O)c1
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: COc1cccc(Nc2cc(F)c(F)cc2C(=O)NOCc2ccccc2)c1
Yield: 105.7 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (2.90 g, 17.6 mmol), 2-(3-methoxy-anilino)-4,5-difluorobenzoic acid (Example Q, 4.48 g, 16 mmol), O-benzylhydroxylamine hydrochloride (2.6 g, 16 mmol), and triethylamine (2.5 mL, 17.6 mmol) provided 6.5 g of the crude title compound.
Reaction SMILES: [C:1]([O:10]C(=O)CCCCC)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[OH-:18].[Na+].Cl>CCO.O>[C:7]([C:7]1[CH:8]=[C:2]([C:1]([OH:10])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1)(=[O:18])[CH2:8][CH2:2][CH2:3][CH3:5]
Reactant: CCCCCC(=O)OC(=O)c1ccccc1O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCC(=O)c1ccc(O)c(C(=O)O)c1
Yield: 90 %

Procedure:
97.5 g of compound 17 (412 mmole) was dissolved in 530 ml EtOH and 1050 ml water. 87 g NaOH (2.19 mole) was added and the mixture was refluxed for 5 hours. Afterwards the mixture was acidified with concentrated HCl to pH 1. The formed precipitate was filtered off and dried under reduced pressure. 82 g was obtained (90% yield).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7](=[NH:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1.[I-].[Zn+2].[I-]>[C:8]1([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([NH2:20])[C:5]#[N:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)C#N
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: N#CC(N)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4.05 ml (0.03 mol) of trimethylsilylcyanide in 20 ml of dry benzene was treated with 0.44 gm (0.001 mol) zinc iodide and 4.63 ml (0.028 mol) of benzophenoneimine. The reaction mixture was stirred at room temperature for 10 min., whereupon a white precipitate formed. The reaction mixture was quenched with wet ether and stirred for 2 hours. The liquid phase was washed with saturated brine solution and dried over sodium sulfate and evaporated in vacuo. The residue was recrystallized from ether-hexane to afford 2.4 gm (38%). 1H NMR (CDCl3, 300 MHz) δ 7.7-7.6 (m, 4H), 7.4-7.28 (m, 6H); 13C NMR (CDCl3, 75.5 MHz ) δ 141.2, 128.9, 128.6, 125.8, 123.4, 60.8.
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][NH:20][CH2:21][CH2:22]N>C(O)C>[CH3:19][N:20]1[CH2:21][CH2:22][NH:18][C:4]1=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CNCCN
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Agent: I
Solvent: CCO
Product: CN1CCNC1=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3 g prepared as described in Example 166), N-methylethylenediamine (2 ml) and absolute ethanol (35 ml) was heated under reflux for 8 hours to give a solid which was recrystallised from ethyl acetate to give 4-[2-(1-methyl-2-imidazolidinylideneamino)phenyl]morpholine (m.p. 156° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@:12]1(C)[C@H:15]([CH:16]2OCOO2)[N:14](C(=O)C(OC)=O)[C:13]1=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[OH:30].[K+].[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH2:29][OH:30])[NH:14][C:13]1=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)N1C(=O)[C@](C)(NC(=O)OCc2ccccc2)[C@@H]1C1OCOO1
Reactant: O=C([O-])O
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: O=C(N[C@H]1C(=O)N[C@@H]1CCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of methyl 2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(1,2,4-trioxolan-3-yl)-methylazetidin-1-yl]-2-oxoacetate (205 mg) in methanol (4 ml) was added 1N aqueous potassium hydrogen carbonate (0.5 ml) at ambient temperature. The mixture was stirred for 25 minutes and cooled to 0° C. Sodium borohydride (40 mg) and 1N aqueous potassium hydrogen carbonate were added to the mixture at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes and at ambient temperature for an additional 30 minutes, and quenched by addition of acetic acid (0.20 ml). The resulting mixture was concentrated under reduced pressure and the residue was dissolved in chloroform and washed with brine containing sodium hydrogen carbonate. The aqueous layer was extracted three times with chloroform. The combined extracts were dried over magnesium sulfate, evaporated in vacuo, and chromatographed on silica gel (3 g, eluting with 10-30% acetone in dichloromethane) to give 66 mg of (3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one.
Reaction SMILES: [F:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]1[NH:13][O:14][CH3:15].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl>[F:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]1[N:13]([O:14][CH3:15])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: CONC1c2ccccc2CCCC1F
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C1c2ccccc2CCCC1F
Temperature: 20 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
To a stirred solution of N-(6-fluoro-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-O-methyl-hydroxylamine (0.100 g; 0.48 mmol), prepared as described in example P2b and triethylamine (0.073 ml; 0.53 mmol) in dichloromethane (1 ml) under nitrogen at 0° C. was added drop wise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.093 g; 0.48 mmol). The reaction mixture was stirred at 20° C. for 15 h under nitrogen. The solvent was removed in vacuo to afford a sticky oil which was subject to flash chromatography (eluant: c-hexane/ethyl acetate 95:5 to 0:100) to afford 0.134 g (76% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (6-fluoro-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-methoxy-amide as an oil.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.[OH-].[Na+].C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[N:10]([CH3:11])[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[CH:5][C:6]=2[N:12]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CNc1ccc(C(=O)OC)cc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)cccc2Cl)nc2cc(C(=O)O)ccc21

Procedure:
Prepared analogously to example 113a from 3-amino-4-methylamino-benzoic acid methyl ester and 1,3-dichloro-2-isothiocyanato-benzene with DCC in DMF and NaOH in ethanol.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([O:20][CH3:21])=[C:5]([C:22]([OH:24])=O)[N:4]=1)#[N:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.Cl.[CH3:41][O:42][C:43](=[O:46])[CH2:44][NH2:45]>ClCCl>[CH3:41][O:42][C:43](=[O:46])[CH2:44][NH:45][C:22]([C:5]1[N:4]=[C:3]([C:1]#[N:2])[C:12]2[C:7]([C:6]=1[O:20][CH3:21])=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:24]
Reactant: COc1c(C(=O)O)nc(C#N)c2c(Oc3ccccc3)cccc12
Reactant: COC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1OC
Temperature: 0 °C
Reaction time: 5.5 h
Yield: 58 %

Procedure:
To a mixture of 1-cyano-4-methoxy-8-phenoxy-isoquinoline-3-carboxylic acid (483 mg, 1.51 mmol), triethylamine (466 μL, 3.32 mmol), and dichloromethane (12 mL) was added isobutylchloroformate (211 μL, 1.62 mmol) at 0° C. The mixture was stirred at 0° C. for twenty-five minutes before glycine methyl ester hydrochloride (208 mg, 1.66 mmol) was added. The mixture was stirred at 0° C. for twenty-five minutes and at room temperature for 5.5 hours before it was concentrated. The residue was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow solid (343 mg): MS: (+) m/z 391.95 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH3:11])=[CH:8][C:9]=1[Cl:10])=[O:4].C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][Br:19])=[CH:8][C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1sc(C)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(CBr)cc1Cl
Yield: 61 %

Procedure:
A mixture of 3-Chloro-5-methyl-thiophene-2-carboxylic acid methyl ester (4.4 g, 23.1 mmol), NBS (5.1 g, 28.85 mmol), and ACHN in CCl4 (40 ml) was refluxed in a pressure tube over the weekend. The reaction mixture was cooled and evaporated. The residue was purified by column (0-5% EtOAc in hexane) to give 3.8 g (61%) yellow solid product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH:12]([C:14]([O:16]C)=[O:15])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>C1COCC1.O>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1CC(c2cccc(C(F)(F)F)c2)=NO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CC(c2cccc(C(F)(F)F)c2)=NO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of methyl 3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylate (2.3 g, 8.4 mmol) in THF (10 mL) was added 2 M of sodium hydroxide in water (10 mL) at 0° C. The reaction mixture was slowly warmed to ambient temperature, stirred for 2 h, neutralized with 2 N HCl to pH 7, and extracted with ethyl acetate (2×50 mL). The organic extracts were combined, washed with saline solution (50 mL), dried over sodium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel, eluting with methylene chloride/methanol (95/5 to 80/20). The appropriate fractions were combined and concentrated in vacuo to give 3-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole-5-carboxylic acid (2.18 g, 100%) as a white crystalline solid. LCMS: 258.2 (M−H−, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].[CH:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1>CC(C)=O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][CH2:26][C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1ccc(Br)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(Br)c(OCc2ccccc2)c1
Yield: 84.3 %

Procedure:
To a suspension of 4.5 g (18.4 mmol) of 6 and 4.1 g (30 mmol) of K2CO3 in 150 ml of acetone under Ar was added 3.4 g (20 mmol) of BnBr. The mixture was heated at reflux for 15 h, concentrated, then diluted with 100 ml of CH2Cl2, washed (water, 1 N HCl, and brine), and dried (Na2SO4). Concentration and chromatography (EtOAc/hexane) afforded 5.2 g (84%) of 7 (white solid): 1H NMR (300 MHz, CDCl3) δ 1.39 (t, J=7.2 Hz, 3 H), 4.37 (q, J=7.2 Hz, 2 H), 5.21 (s, 2 H), 7.39 (m, 3 H), 7.50 (in, 3 H), 7.63 ppm (m, 2 H).
Reaction SMILES: [C:1]1([C:13](=O)[C:14](OC)=[O:15])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:20]1>>[C:1]1([C:13]2[C:14](=[O:15])[NH:31][C:29](=[O:30])[C:28]=2[C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CCC2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12

Procedure:
In one embodiment, the method of the present invention comprises a step of dissolving methyl 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl-oxoacetate and indole-3-acetamide in an organic solvent and adding the obtained solution to a base, and reacting methyl 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl-oxoacetate and indole-3-acetamide to form highly pure 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15]CC2C=CC=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(COCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reaction time: 4 h

Procedure:
To a stirring solution of (+/−)-N-(t-butoxycarbonyl)-2-(phenylmethoxymethyl)-morpholine (595 mg, 1.94 mmol) and 20% palladium on carbon (120 mg, Aldrich) in MeOH (20 mL) was added 50 psi of hydrogen. The reaction was stirred for 4 h. The reaction was filtered and the filtrate was conc. in vacuo to a colorless oil. The oil can be used without further purification. MS (CI) 218 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[CH3:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: Cc1ccc(B(O)O)cc1Cl
Product: Cc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 94.1 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 2.49 g (7.17 mmol) of 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.59 g (9.33 mmol) of 3-chloro-4-methylphenylboronic acid (Step 1). Purification by silica gel chromatography (HPLC) with ethyl acetate/hexane (1:5) gave 2.65 g (94%) of 1-(3-chloro-4-methylphenyl)-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 138.0°-139.0° C.; NMR (CDCl3) δ 2.34 (s, 3H), 3.05 (s, 3H), 6.75 (dd, J=2, 8 Hz, 1H), 7.03-7.10 (m, 2H), 7.18-7.26 (m, 2H), 7.29 (d, J=8 Hz, 2H), 7.83 (d, J=8 Hz, 2H). MS (FAB): m/e 399 (M+Li). Anal. Calc'd for C20H15 ClF2O2S: C, 61.15; H, 3.85. Found: C, 61.12; H, 3.82.
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19]C)=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].CO.O.[OH-].[Li+].Cl>O>[CH2:10]([O:9][C:7]([N:3]1[CH2:4][CH2:5][CH2:6][C:2]1([CH3:1])[C:17]([OH:19])=[O:18])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C1(C)CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To the solution of 1-benzyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate (3.1 g, 10.8 mmol) in the mixture of Methanol (20 mL) and water (20 mL) was added lithium hydroxide monohydrate (0.9 g, 21.6 mmol). The mixture was stirred at 30° C. for 3 h. The resulting mixture was treated with 5N hydrochloric acid to pH=2 and filtrated, washed with water, dried in vacuum at 45° C. 1.9 g of 1-(benzyloxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid was obtained. Yield: 67%. LC-MS (ESI) m/z: 264 (M+1)+.