Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[N:15][N:16]([CH3:18])[N:17]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(-c2nnn[nH]2)ccc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(-c2nnn(C)n2)ccc1OC
Temperature: 25 °C

Procedure:
Methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate (0.78 g, 3.33 mmol) methyl iodide (0.21 mL, 3.33 mmol) and potassium carbonate (0.46 g, 3.33 mmol) were combined in acetone (8 mL) and heated at reflux overnight. After cooling to room temperature, the mixture was filtered and concentrated. Flash chromatography on silica gel afforded 170 mg (21%). LC/MS (HPLC method 3): tR=2.01 min, 249.09 (MH)+
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].C([Li])CCC.[Br:16][CH2:17][CH2:18][CH2:19]Br>O1CCOCC1>[Br:16][CH2:17][CH2:18][CH2:19][NH:4][C:3]1[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=1[Cl:1]
Reactant: Cc1cc(C)c(N)c(Cl)c1
Reactant: BrCCCBr
Agent: [Li]CCCC
Solvent: C1COCCO1
Product: Cc1cc(C)c(NCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.1 %

Procedure:
To a solution of the 2-chloro-4,6-dimethyl aniline (16.9 g g, 108 mmol) in 1,4-dioxane (80 mL) was added n-butyl lithium solution (2.5 M in hexanes, 48 mL), dropwise, at 0° C. under argon. The reaction mixture was warmed up to rt and stirred for 20 min. 1,3-Dibromopropane (109 g, 543 mmol) was added and the reaction mixture was stirred overnight. The mixture was filtered through celite and concentrated. Purification was carried out by reverse phase chromatography using water, methanol and trifluoroacetic acid to obtain product (20.01 g, 72.5 mmol, 67%) as brown oil. LC/MS: tR=1.5 min. [M+H] 277. 1H NMR (CD3OD) δ: 7.12 (s, 1H), 6.99 (s, 1H), 3.52 (t, J=6.65 Hz, 2H), 3.36 (t, J=6.75 Hz, 2H), 2.36 (s, 3H), 2.29 (s, 3H), 2.14 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9].[Cl:15][S:16](O)(=[O:18])=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:4][C:3]=1[S:8]([C:11]([F:12])([F:13])[F:14])(=[O:9])=[O:10]
Reactant: O=S(=O)(O)Cl
Reactant: O=S(=O)(c1ccccc1F)C(F)(F)F
Product: O=S(=O)(Cl)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1

Procedure:
reacting 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene, and chlorosulfonic acid at about 110° C. to about 130° C. to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride and isolating or not isolating the 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride;
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]Cl>C(O)CCC>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Brc1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-aniline (2 g, 1.162 mmol) was taken in dry nBuOH (25 mL) and dry potassium carbonate (4.8 g, 34.8 mmol) was added to it and stirred at rt for 1 h under nitrogen. Bis-(2-chloroethyl) amine hydrochloride 2 (2.49 g, 13.9 mmol) in nBuOH (10 mL) was then added to the mixture through a syringe. The reaction mass was then heated at 100° C. for 12 h. nBuOH was evaporated in vacuo and the residue was extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded the crude product that on purification silica gel column (chloroform/methanol) afforded the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10](O)=[O:11])[N:5]=[CH:4][C:3]=1[NH:13][C@@H:14]1[CH2:19][C@@H:18]2[CH2:20][C@@H:16]([C:17]2([CH3:22])[CH3:21])[C@H:15]1[CH3:23].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:13][C@@H:14]1[CH2:19][C@@H:18]2[CH2:20][C@@H:16]([C:17]2([CH3:21])[CH3:22])[C@H:15]1[CH3:23]
Reactant: C1COCCN1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)O)c(=O)c1Br)C2(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)N3CCOCC3)c(=O)c1Br)C2(C)C
Yield: 56.6 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid (30 mg, 0.078 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22 mg, 0.117 mmol), 1-hydroxybenzotriazole anhydride (16 mg, 0.117 mmol) and triethylamine (16 μL, 0.117 mmol) in N,N-dimethylformamide (0.3 mL) was stirred with morpholine (10 μL, 0.117 mmol) at room temperature for 5 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium sulfate and saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/ethyl acetate=1/1) to give the desired product (20 mg, 57% yield).
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:17][C:18]1[N:23]=[C:22]([S:24][CH3:25])[N:21]=[C:20]([Sn](CCCC)(CCCC)CCCC)[N:19]=1.[F-].[Cs+].C1COCC1>O.[Cu]I.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>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([NH:8][C:3]2[C:2]([C:20]3[N:19]=[C:18]([CH3:17])[N:23]=[C:22]([S:24][CH3:25])[N:21]=3)=[CH:7][N:6]=[CH:5][N:4]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(Nc2ncncc2Br)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(C)nc(SC)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncncc2-c2nc(C)nc(SC)n2)cn1
Temperature: 140 °C
Yield: 53.7 %

Procedure:
A glass microwave reaction vessel was charged with 5-bromo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (23 mg, 0.082 mmol), 2-methyl-4-(methylthio)-6-(tributylstannyl)-1,3,5-triazine (35.2 mg, 0.082 mmol), copper(I) iodide (15 mg, 0.082 mmol), cesium fluoride (206 mg, 0.82 mmol) and tetrakis(triphenylphosphine)palladium(0) (9.45 mg, 8.18 μmol) and THF (1 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 30 min. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude product as a light-yellow solid. The crude product was purified by silica gel chromatography eluting with 60% EtOAc/hexanes to give N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (15 mg, 0.044 mmol, 53.7% yield). 1H NMR (300 MHz, CDCl3) δ 11.58 (s, 1H); 9.65 (s, 1H); 8.74 (s, 1H); 8.35 (d, J=2.19 Hz, 1H); 8.07 (dd, J=8.84, 2.56 Hz, 1H); 6.82 (d, J=8.92 Hz, 1H); 3.96 (s, 3H); 2.67 (s, 3H); 2.65 (s, 3H). m/z (ESI, +ve ion) 342.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[N:10]([O-])=O.[Na+]>C(O)(=O)C.O>[C:6]([N:7]=[N+:8]=[N-:10])(=[O:9])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N=[N+]=[N-]
Reaction time: 0.5 h

Procedure:
25 g (0.19 mol) of t-butylcarbazate was dissolved in 80 mL of acetic acid and 160 mL of water, and 15 g (0.22 mol) of sodium nitrite was added in small portions under cooling with ice. The reaction solution was stirred for 30 minutes under cooling with ice and extracted with 250 ml of diisopropyl ether. The organic layer was washed with 200 mL of saturated aqueous sodium hydrogen carbonate twice and with 100 mL of saturated aqueous sodium chloride once successively, dried over anhydrous sodium sulfate and filtered to give a solution of t-butyl carbonazidate in diethyl ether
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:26][O:27][CH3:28])[C:12]([NH:14][C@H:15]2[C@@H:18]([S:19][CH3:20])[N:17]([S:21]([O-:24])(=[O:23])=[O:22])[C:16]2=[O:25])=[O:13])[N:10]=1)=O.[Na+:29].CSC(=S)N.[Na]>O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:26][O:27][CH3:28])[C:12]([NH:14][C@H:15]2[C@@H:18]([S:19][CH3:20])[N:17]([S:21]([O-:24])(=[O:23])=[O:22])[C:16]2=[O:25])=[O:13])[N:10]=1.[Na+:29]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1SC)c1csc(NC(=O)CCl)n1
Agent: CSC(N)=S
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@@H]1SC)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.6 %

Procedure:
To a solution of 0.250 g of sodium (3R,4R)-3-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-4-methylthio-2-oxoazetidine-1-sulfonate in 8 ml of water is added under ice-cooling 0.078 g of sodium monomethyldithiocarbamate, and the mixture is stirred at room temperature for 1.5 hours. The same procedure as Example 3B yields 0.052 g of sodium (3R,4R)-3-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-4-methylthio-2-oxoazetidine-1-sulfonate.
Reaction SMILES: CS[C:3]1[C:12]2[N:13]=[CH:14][NH:15][C:11]=2[C:10]2[N:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].[ClH:24].BrC1C=C(C=CC=1)N>CN1CCCC1=O>[ClH:24].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[C:12]2[N:13]=[CH:14][NH:15][C:11]=2[C:10]2[N:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]=1
Reactant: CSc1cc2cncnc2c2[nH]cnc12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: Brc1cccc(Nc2cc3cncnc3c3[nH]cnc23)c1
Temperature: 120 °C
Yield: 61.1 %

Procedure:
A mixture of 4-methylthioimidazo[4,5-h]quinazoline (0.216 g, 1 mmol), 3-bromoaniline (0.25 g, 1.5 mmol), and 3-bromoaniline hydrochloride (0.31 g, 1.5 mmol) in N-methylpyrrolidone (50 mL) is heated 120° C. for 2 h. The solvent is removed under vacuum and the residue is triturated with EtOH to give a solid which is recrystallized from MeOH to give 4-(3-bromoanilino)imidazo[4,5-h]quinazoline hydrochloride (0.23 g, 61%). 1H NMR (DMSO) δ11.11 (1H, brs), 8.93 (2H, s), 8.66 (1H, d, J=9.0 Hz), 8.11 (1H, brs), 8.07 (1H, d, J=9.0 Hz), 7.83 (1H, brd, J=6.8 Hz), 7.50-7.40 (2H,m).
Reaction SMILES: [Cu][C:2]#[N:3].N(OC(C)(C)C)=O.[CH:11]([C:14]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[C:16]([O:26][CH3:27])[C:15]=1N)([CH3:13])[CH3:12].Cl>CS(C)=O>[CH:11]([C:14]1[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[C:16]([O:26][CH3:27])[C:15]=1[C:2]#[N:3])([CH3:13])[CH3:12]
Reactant: N#C[Cu]
Reactant: COc1cc(N2CCOCC2)cc(C(C)C)c1N
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CS(C)=O
Product: COc1cc(N2CCOCC2)cc(C(C)C)c1C#N
Temperature: 50 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
Copper(I) cyanide (1.07 g, 11.9 mmol) is added to dimethylsulfoxide (15 ml) at 50° C. followed by the addition of tert-Butyl nitrite (3.8 ml, 27.6 mmol) at once. A solution of (2-isopropyl-6-methoxy-4-morpholin-4-yl-phenyl)-amine (2.3 g, 9.2 mmol) in dimethylsulfoxide (15 ml) is added drop wise via an addition funnel to the above mixture. After completion of the addition, the reaction mixture is allowed to stir for 1 h at 50° C. After being cooled to 45° C., the reaction mixture is slowly treated with 5N hydrochloric acid and cooled to ambient temperature. The resulting mixture is extracted with ethyl acetate (3×50 ml). The combined organic layers are washed with water (30 ml), brine (30 ml), dried over sodium sulfate and evaporated to dryness. The crude product is purified by flash column chromatography (silica gel, 20% ethyl acetate/hexane) to afford 2-isopropyl-6-methoxy-4-morpholin-4-yl-benzonitrile (0.4 g, 1.54 mmol, 17%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH2:7][C:8]#[CH:9])[C:3]1=[O:18].I[C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:21]=1.C(NC(C)C)(C)C.O>COC(C)(C)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])([CH2:7][C:8]#[C:9][C:20]2[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)[N:21]=2)[C:3]1=[O:18]
Reactant: C#CC[C@]1(NC(=O)OC(C)(C)C)CCN(C)C1=O
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)NC(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Reaction time: 0.33 h
Yield: 88.4 %

Procedure:
In a 5 L three-necked flask with overhead paddle stirrer and a nitrogen inlet. tert-butyl N-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 4) (104.79 g, 415.32 mmol) was suspended in tert-Butyl methyl ether (2100 mL). 2-Iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (which may be prepared as described in Description 12) (166.34 g, 456.85 mmol) was added followed by diisopropylamine (174.63 mL, 1246 mmol) and the mixture was stirred over 20 mins. To the suspension was added copper iodide (1.58 g, 8.31 mmol) followed by bis(triphenyl-phosphine)palladium (II) dichloride (2.92 g, 4.15 mmol) and the mixture was stirred at room temperature for 3 hours. Water (1000 mL) was added and the mixture stirred for 30 mins. The phases were separated and the organic phase, washed with water (2×500 mL), dried over magnesium sulphate, filtered and evaporated to a tan foam, 230 g. The material was purified in three batches of approximately 75 g by column chromatography using an 800 g (Biotage 75L) column and eluting with a gradient of acetone in iso-hexane. This gave the title compound (D13a) (179.3 g) in good purity by NMR and consistent spectroscopically with that produced by Method 1 and the R isomer in Description 13.
Reaction SMILES: [CH2:1]([C:4]1[C:21]2[CH2:20][C:19]3[C:14](=[C:15]([CH2:31][CH2:32][CH3:33])[C:16]([CH2:28][CH2:29][CH3:30])=[C:17]([CH2:25][CH2:26][CH3:27])[C:18]=3[CH2:22][CH2:23][CH3:24])[CH2:13][C:12]=2[C:11]([CH2:34][CH2:35][CH3:36])=[C:10]2[C:5]=1[CH:6]=[C:7]([I:38])[C:8]([I:37])=[CH:9]2)[CH2:2][CH3:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[I:37][C:8]1[C:7]([I:38])=[CH:6][C:5]2[C:10](=[C:11]([CH2:34][CH2:35][CH3:36])[C:12]3[C:21]([C:4]=2[CH2:1][CH2:2][CH3:3])=[CH:20][C:19]2[C:14](=[C:15]([CH2:31][CH2:32][CH3:33])[C:16]([CH2:28][CH2:29][CH3:30])=[C:17]([CH2:25][CH2:26][CH3:27])[C:18]=2[CH2:22][CH2:23][CH3:24])[CH:13]=3)[CH:9]=1
Reactant: CCCc1c(CCC)c(CCC)c2c(c1CCC)Cc1c(c(CCC)c3cc(I)c(I)cc3c1CCC)C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCCc1c(CCC)c(CCC)c2cc3c(CCC)c4cc(I)c(I)cc4c(CCC)c3cc2c1CCC
Yield: 34.1 %

Procedure:
6,11-Dihydro-5,7,8,9,10,12-hexapropyl-2,3-diiodonaphthacene (0.23 8 g, 0.324 mmol), 2,3-dichloro-5,6-dicyanobenzoquinone (0.081 g, 0.35 mmol) and 1,4-dioxane (2 ml) were charged in a reactor. The mixture was refluxed for 3 hours. After cooling, the precipitates were removed by filtration. The solvent in the mixture was removed in vacuum followed by recrystallization from chloroform/methanol. The orange red title compound (0.081 g) was obtained. The isolation yield was 34%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[C:11]2[CH3:28])=[CH:4][CH:3]=1.[N:30]([C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[C:31]=[O:32]>>[CH3:28][C:11]1[N:10]([CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:31]([NH:30][C:33]3[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=3)=[O:32])=[CH:7][CH:6]=2)=[O:29])[C:14](=[O:15])[C:13]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(N)cc1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CC(=O)c1ccc(NC(=O)Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Synthesis in analogy to Example 6 starting from 3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one and 1-isocyanato-4-nitro-benzene to yield 1-{4-[2-(2-methyl-5-oxo-4,4-diphenyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-3-(4-nitro-phenyl)-urea. LC/MS at 254 nm; [M+H] 548; Rt 3.601 min.
Reaction SMILES: [NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[CH:5][C:4]=1OC.C(C1C=C(C=CC=1)[CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])#N>>[NH2:1][C:2](=[N:15][OH:16])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:11][CH:12]=1)[CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: COC(=O)c1ccc(C(N)=NO)c(OC)c1
Reactant: COCCN(Cc1cccc(C#N)c1)C(=O)OC(C)(C)C
Product: COCCN(Cc1cccc(C(N)=NO)c1)C(=O)OC(C)(C)C

Procedure:
Title compound was prepared following procedure and work up described for Intermediate 47 step 2 but starting from tert-Butyl 3-cyanobenzyl(2-methoxyethyl)carbamate obtained in step 2 (7.4 g, 0.0254 mol) (RT for 12 h). Title compound was obtained as a pale yellow gummy liquid (7.1 g, 86%). 1H NMR (DMSO-d6, 400 MHz) δ 9.59 (s, 1H), 7.52-7.54 (m, 2H), 7.30-7.34 (m, 1H), 7.19-7.21 (m, 1H), 5.75 (s, 2H), 4.40 (s, 2H), 3.37-3.40 (m, 2H), 3.21-3.30 (m, 5H), 1.32-1.41 (m, 9H). LC/MS (Method A): 324.0 (M+H)+. HPLC (Method B) Rt 5.23 min (Purity: 96.2%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@H:3]([O:10][C:11](=[O:26])[C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>[Pd].C(O)C>[F:1][C:2]([F:27])([F:28])[C@H:3]([O:10][C:11](=[O:26])[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [H][H]
Reactant: CCCCCC[C@@H](OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCCCCC[C@@H](OC(=O)c1ccc(O)cc1)C(F)(F)F

Procedure:
The resulting ester compound and 0.13 g of 10% palladium-on-carbon were added to ethanol to conduct debenzylation in a hydrogen atmosphere to obtain 0.39 g of (R)-(+)-4-hydroxybenzoic acid 1-trifluoromethylheptyl ester ##STR7##
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[S:8][C:7]=1[C:14]([O:16]C)=[O:15])[CH3:3].[OH-].[Na+]>CO>[CH3:3][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[S:8][C:7]=1[C:14]([OH:16])=[O:15])[CH3:1]
Reactant: COC(=O)c1sc([N+](=O)[O-])cc1N=NN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)N=Nc1cc([N+](=O)[O-])sc1C(=O)O
Reaction time: 14 h
Yield: 86.5 %

Procedure:
To a solution of methyl 3-[(dimethylamino)diazenyl]-5-nitrothiophene-2-carboxylate (550 mg) in methanol (10 mL) was added an aqueous solution of sodium hydroxide (0.25 g in 5 mL of water) at rt and stirred the mixture for 14 h. Excess of methanol was evaporated under reduced pressure and the residue was diluted with ice cold water. The solution was acidified with dil. HCl and the solid separated was filtered, washed with water and dried to give the product as a yellow color solid (450 mg, 86%). The crude product was recrystallized from chloroform-methanol (290 mg), mp 184-186° C. 1H NMR (400 MHz, DMSO-d6): δ 13.26 (1H, br s), 8.00 (1H, s), 3.59 (3H, s), 3.25 (3H, s); LC-MS (positive ion mode): m/z 245 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2].C[O:30]C1C=C2C(=CC=1OC)C(C(=O)C1C=CC=C(OC)C=1)=NC=C2CC(O)=O.[Se](=O)=O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:30])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1cccc(C(=O)c2ncc(CC(=O)O)c3cc(OC)c(OC)cc23)c1
Reactant: CCOC(=O)c1cnc(Cc2cccc(OC)c2)c2cc(OC)c(OC)cc12
Agent: O=[Se]=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc(C(=O)c2cccc(OC)c2)c2cc(OC)c(OC)cc12
Yield: 82 %

Procedure:
1-(3-methoxybenzyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester (159 mg, 0.417 mmol, the intermediate in the preparation of [6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinolin-4-yl]-acetic acid) (Example 7) was dissolved into 4 ml of acetic acid. Then selenium dioxide (69.5 mg, 1.50 eq) was added. The mixture was refluxed for 20 minutes and then evaporated to dryness. The residue was suspended into ethyl acetate and the mixture was passed through a layer of silica gel. The filtrate was evaporated to give 1-(3-methoxybenzoyl)-6,7-dimethoxyisoquinoline-4-carboxylic acid ethyl ester as a solid (135 mg, 82%). This material (95.6 mg, 0.242 mmol) was suspended into 5 ml of methanol. Then 1N sodium hydroxide solution (0.5 ml) was added. The mixture was refluxed for 1 hr. TLS showed complete disappearance of the starting material. The mixture was evaporated and the residue was dissolved into 5 ml of water and then filtered. The filtrate was acidified with 1N hydrochloric acid to give 6,7-Dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid as a solid (76 mg, 86%). ES-MS calculated for C20H17NO6 (m/e) 367.36, observed 368.4 (M+1). 1H-NMR is consistent with the desired structure.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2].Cl.[CH3:21][O:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([N:27]2[CH2:26][CH2:25][C:24]3[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=3[O:22][CH3:21])[CH2:28]2)=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: CC(=O)NCCc1nc(C(=O)O)c2ccccc2n1
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(CCNC(C)=O)nc3ccccc13)C2
Yield: 17 %

Procedure:
Reaction of 2-(2-(acetamido)ethyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 76 (17% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.74-1.75 (m, 3H), 2.69 and 2.95 (2t, 2H), 3.14-3.19 (m, 2H), 3.45 and 3.99 (2t, 2H), 3.57-3.61 (m, 2H), 3.74-3.80 (3s, 6H), 4.36 and 4.89 (2s, 2H), 6.64 and 6.99 (2d, 1H), 6.82 and 7.05 (2d, 1H), 7.67-7.75 (m, 1H), 7.85-7.94 (m, 2H), 8.02-8.06 (m, 2H); MS (ESI) m/z 435 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=3)=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=2)=[C:20]([C:35]([F:36])([F:37])[F:38])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: Cc1cccc(C=CCOc2ccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)cc2C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: Cc1cccc(C=CCOc2ccc(CCC(N)(CO)CO)cc2C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Compound 103-3 (410 mg) was dissolved in ethanol (25 ml), concentrated hydrochloric acid (3.0 ml) was added, and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (135 mg) as a white powder.