Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:22]([NH:24][CH:25]([C:34](=[O:38])[CH:35]=[N+]=[N-])[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:23])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:39])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:40].C(O)(=O)C>ClCCl>[Br:40][CH2:35][C:34](=[O:38])[CH:25]([NH:24][C:22]([CH:18]1[N:15]2[C:16](=[O:17])[CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:11][CH2:12][C:13](=[O:39])[N:14]2[CH2:21][CH2:20][CH2:19]1)=[O:23])[CH2:26][C:27]([OH:29])=[O:28]
Reactant: Br
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)CBr
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 506a (2.27 g, 4.2 mmol) in dry dichloromethane (50 ml) was treated with 30% hydrobromic acid in acetic acid (1.84 ml, 9.2 mmol, 2.2 equiv) at 0° C., under nitrogen. After 10 min stirring at 0° C. the reaction was complete and a white solid crystallised in the medium. The solid was filtered and washed with ethylacetate and diethylether to afford 2.20 g (100%) of [3S(1S,9S)] 5-bromo-3-(9-benzoylamino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxamido)-4-oxopentanoic acid which was used without further purification: 1H NMR (D6-DMSO) δ 8.87 (1H, d, J=7.3), 8.63 (1H, d, J=7.6), 7.91-7.87 (2H, m), 7.60-7.44 (3H, m), 6.92 (1H, bs), 5.14-5.09 (1H, m), 4.92-4.65 (2H, m), 4.43 (2H, AB), 4.41-4.35 (1H, m), 3.33-3.22 (1H, m), 2.98-2.90 (1H, m), 2.89-2.57 (2H, m), 2.35-2.15 (3H, m), 1.99-1.91 (2H, m), 1.75-1.60 (2H, m). A solution of the bromoketone (535 mg, 1 mmol) in dry DMF (10 ml) was treated with potassium fluoride (150 mg, 2.5 mmol, 2.5 equiv), under nitrogen. After 5 min stirring at room temperature, 2-mercaptothiazole (140 mg, 1.2 mmol, 1.2 equiv) was added. After overnight reaction ethylacetate (150 ml) was added and the organic solution was washed with brine, dried over magnesium sulphate and reduced in vacuo. The residue was crystallised in diethyl ether, filtered and purified on silica gel using a gradient of MeOH (0% to 5%) in dichloromethane. Evaporation afforded 344 mg (60%) of a white solid: mp. 90-95° C. (decomp.); [α]D20 −82° (c 0.2, CH2Cl2)); IR (KBr) 3328, 2941, 1745, 1659, 1535, 1422, 1276, 1255, 1223, 1072; 1H NMR (D6-DMSO)δ 8.92 (1H, d, J=7.6), 8.68 (1H, d, J=7.6), 7.98-7.90 (2H, m), 7.75-7.67 (1H, m), 7.64-7.50 (4H, m), 5.22-5.18 (1H, m), 4.95-4.74 (2H, m), 4.58-4.38 (3H, m), 3.52-3.19 (1H, m), 3.05-2.65 (4H, m), 2.40-1.50 (6H, m). Anal. Calcd for C25H27N5O4S2.H2O: C, 50.75; H, 4.94 N, 11.84. Found: C, 51.34; H, 4.70; N, 11.58. MS (ES+) 572.
Reaction SMILES: C([O:8][C:9](=[O:46])[CH2:10][CH2:11][NH:12][C:13](=[O:45])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:44])[C@H:22]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:43])[NH:39][N+]([O-])=O)[NH:23]C(OCC2C=CC=CC=2)=O)[CH:15]=1)C1C=CC=CC=1>C(O)=O.[Pd]>[CH:9]([OH:46])=[O:8].[NH2:23][C@H:22]([C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][CH2:11][CH2:10][C:9]([OH:46])=[O:8])=[O:45])=[O:44])[CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:43]
Reactant: N=C(NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1)N[N+](=O)[O-]
Agent: [Pd]
Solvent: O=CO
Product: N=C(N)NCCC[C@H](N)C(=O)Nc1cccc(C(=O)NCCC(=O)O)c1
Yield: 187 %

Procedure:
900 mg of N-[m-[[N2 -[(benzyloxy)carbonyl]-N5 -(N-nitroamidino)-L-ornithyl]amino]benzoyl]-β-alanine benzyl ester and 300 mg of Pd/C (5%) are stirred in 20 ml of formic acid for 18 hours under hydrogen. The reaction mixture is filtered and the filtrate is evaporated in a vacuum. The residue is taken up in water and again evaporated in a vacuum. After drying there are obtained 545 mg of N-[m-(L-arginylamino)benzoyl]-β-alanine formate (2:3), [α]D20 =+39° (H2O, c=0.5%).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][N:9]=1)=[O:7])(C)(C)C.COC1C=CC=C(OC)C=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[C:15]([C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=1)#[N:16]
Reactant: Cc1cc(C#N)cnc1C(=O)OC(C)(C)C
Agent: COc1cccc(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)cnc1C(=O)O
Reaction time: 6.5 h

Procedure:
To a solution of 5-cyano-3-methyl-pyridine-2-carboxylic acid tert-butyl ester (8.50 g, 38.9 mmol) in 1,3-dimethoxybenzene (51 ml, 389 mmol) was added TFA (85 ml) and stirred for 6.5 h. The reaction mixture was diluted with toluene and evaporated. The residue was taken up in toluene and evaporated (2×). The product was crystallized from TBME/hexanes to give the title compound as a white powder. HPLC: RtH1=2.314 min; ESIMS [M+Na]+=163; 1H-NMR (360 MHz, CDCl3): δ 8.77 (s, 1H), 8.07 (s, 1H), 2.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17](=O)[C:18]([OH:20])=[O:19]>C(#N)C>[CH2:12]([O:11][C:9]([C:7]1[CH:6]=[N:5][N:4]([CH2:3][C:2]2[S:14][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[N:1]=2)[CH:8]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Reactant: O=C(O)C(=O)CBr
Solvent: CC#N
Product: CCOC(=O)c1cnn(Cc2nc(C(=O)O)cs2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution (9 mL) of the compound (2.0 g, 9.38 mmol) obtained in Example 1b in acetonitrile was added 3-bromo-2-oxopropanoic acid (1.9 g, 11.3 mmol), and the mixture was stirred at 80° C. for 2 hr. The resulting crystals were collected by filtration and washed with hexane to give the title compound (2.56 g, 97%) as pale-brown crystals.
Reaction SMILES: [F:1][C:2]([C:16](OC)=[O:17])=[CH:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]3[O:13][CH2:14][O:15][C:9]=3[CH:8]=2)[CH2:6][CH2:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:1][C:2]([CH2:16][OH:17])=[CH:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]3[O:13][CH2:14][O:15][C:9]=3[CH:8]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)C(F)=CC1(c2ccc3c(c2)OCO3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(F)=CC1(c2ccc3c(c2)OCO3)CC1
Yield: 89 %

Procedure:
The method of Example 9 was repeated using 1-(2-Fluoro-2-(methoxy-carbonyl)ethenyl)-1-(3,4-methylene-dioxyphenyl)cyclopropane (Example 6) (0.98 g), diethyl ether (15 ml) and lithium aluminium hydride (0.37 g) to yield the title compound (0.78 g, 88%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][O:10][C:9]2=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[NH:17][C:16]1=[O:25])=[O:4].[OH2:26]>N1CCOCC1>[Cl:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:25])[C:15]2=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:5]3[CH2:6][CH2:14][O:26][CH2:2][CH2:3]3)[CH:7]=2)[CH2:11][O:10]1
Reactant: O
Reactant: O=C(CBr)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Solvent: C1COCCN1
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 94 %

Procedure:
A mixture of 2-bromo-N-[3-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-acetamide (63 mg, 0.15 mmol) in morpholine (1 ml) was stirred at 40° C. under nitrogen for 40 minutes. The mixture was poured into water (75 ml). The solid was filtered, washed with water and dried under vacuum to give N-[3-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-2-morpholin-4-yl-acetamide as a yellow solid (60 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][OH:7]>CC(C)=O>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7]
Reactant: COc1cc(CO)cc(OC)c1OC
Solvent: CC(C)=O
Product: COc1cc(C=O)cc(OC)c1OC
Reaction time: 0 h
Yield: 76 %

Procedure:
Using a similar method to Example 1, a mixture of 400 parts of 3,4,5-trimethoxybenzyl alcohol and 400 parts of acetone with 380 parts of air is passed per hour over the catalyst at 530° C. and 1.2 bar. The residence time is 0.04 second and the throughput is 0.57 tonne/m2.h. 302 parts of 3,4,5-trimethoxybenzaldehyde (in the form of a 44 percent strength by weight solution) are obtained per hour, corresponding to a yield of 76% of theory. The conversion is 95 percent and the space-time yield is 14 grams of 3,4,5-trimethoxybenzaldehyde per cm3 of catalyst volume per hour.
Reaction SMILES: [C:1]([CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)(=O)[CH3:2].C([O-])(C)=O.[NH4+].[BH3-]C#[N:27].[Na+].O>C1COCC1.CO>[NH2:27][CH:1]([CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)[CH3:2]
Reactant: CC(=O)C1CN(C(=O)OCc2ccccc2)CCO1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(N)C1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 50 h
Yield: 39.8 %

Procedure:
To a solution of benzyl 2-acetylmorpholine-4-carboxylate (5.0 g, 19 mmol) in THF/MeOH (1/5, 100 mL) were added AcONH4 (14.6 g, 190 mmol) and NaBH3CN (11.8 g, 190 mmol). The mixture was stirred at room temperature for 50 hr. The mixture was concentrated to give the crude. Water (20 mL) was added and the mixture was extracted by ethyl acetate (60 mL*3), 1N HCl, was added into the combined organic layers. The aqueous layer was concentrated, brought to above pH>8 with 2N NaOH and extracted by ethyl acetate (60 mL*3). The organic layer was washed with brine, dried over sodium sulfate. The mixture was concentrated to give benzyl 2-(1-aminoethyl)morpholine-4-carboxylate (2.0 g, 40%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:11](O)[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1C=CC=CC=1.ClCCCl>[C:5]1([CH:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OC(Cn1cncn1)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: c1ccccc1
Product: c1ccc(C(Cn2cncn2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
26.7 g (0.2 mole) of AlCl3 were added in portions to a solution of 18.9 g (0.1 mole) of 1-phenyl-2-(1,2,4-triazol-1-yl)-ethanol in 50 ml of benzene and 50 ml of 1,2-dichloroethane at -10° C. Thereafter, the mixture was warmed to room temperature in the course of 30 minutes, and was then heated to 80° C., until the evolution of gas was no longer observed. The mixture was poured onto 200 ml of ice-water, the organic phase was separated off and concentrated, and the residue was triturated with diisopropyl ether. Yield 21.4 g (86% ), m.p. 107°-108° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C@H:10]2[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([CH3:23])[CH2:12][CH2:11]2)[CH:4]=1)#[N:2].[ClH:24]>C(Cl)Cl>[ClH:24].[CH3:23][C@H:13]1[NH:14][CH2:15][C@H:10]([O:9][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][N:6]=2)[CH2:11][CH2:12]1
Reactant: C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of tert-butyl (2R,5R)-5-[(4-cyanopyridin-2-yl)oxy]-2-methylpiperidine-1-carboxylate (5.42 g, 17.1 mmol) in CH2Cl2 (8 mL) was cooled at −78° C. and treated with HCl (4 M in dioxane, 30 mL, 120 mmol). The reaction was allowed to warm to RT. After 40 mins, the reaction was concentrated in vacuo and the resulting residue was slurried in Et2O for several hours. The resulting mixture was filtered and the solids washed with Et2O, providing the crude titled compound which was used without further purification. LRMS m/z (M+H) 218.3 found, 218.1 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:9](=O)[NH:8][CH2:7][CH2:6]2.CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:9][NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])C(=O)NCC2
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2c(cc1[N+](=O)[O-])CNCC2
Yield: 83.9 %

Procedure:
A solution of 6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-isoquinolinone (7 g, 31.5 mmol) in THF (800 mL) was treated with 2M BH3 in THF(78.8 mL, 157.6 mmol) and heated to reflux for 20 h. Methanol (100 mL) was added and the solution was concentrated under reduced pressure. The resulting residue was heated with 2N HCl for 3 hr., cooled, basified via careful addition of aqueous ammonium hydroxide, and extracted with dichloromethane. The organic layer was dried, filtered, and taken to a residue under reduced pressure to afford 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (5.5 g crude, 84.5% pure).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:20][CH:21]([O:23][C:24](=[O:41])[NH:25][C@H:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33](Br)[CH:34]=2)[N:29]([C:37](=[O:39])[CH3:38])[C@@H:28]([CH3:40])[CH2:27]1)[CH3:22].C([O-])(O)=O.[Na+]>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.C(Cl)Cl.O1CCOCC1>[C:37]([N:29]1[C:30]2[C:35](=[CH:34][C:33]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:32][CH:31]=2)[C@H:26]([NH:25][C:24](=[O:41])[O:23][CH:21]([CH3:20])[CH3:22])[CH2:27][C@@H:28]1[CH3:40])(=[O:39])[CH3:38]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1OC
Temperature: 100 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A flask was charged with 2-[3,4-bis(methyloxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.429 g, 1.625 mmol), 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 100) (0.5 g, 1.354 mmol), a saturated NaHCO3 aqueous solution (1.5 mL, 1.354 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium(II)-DCM adduct (0.111 g, 0.135 mmol) then filled with 1,4-dioxane (7 mL). The resulting mixture was degassed by bubbling nitrogen in to it, stirred at 100° C. for 1 hr under microwave irradiation then cooled to room temperature. The reaction mixture was filtered through celite and concentrated in vacuovacuo. The residue was partitioned between EtOAC (30 mL) and water (30 mL) and the layers were separated. The organic phase was washed with brine (25 mL) dried over MgSO4 and concentrated in vacuovacuo. Purification of the residue by flash chromatography on silica gel (gradient:0 to 60% AcOEt in Hexanes) gave 1-methylethyl {(2S,4R)-1-acetyl-6-[3,4-bis(methyloxy)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (327 mg, 0.766 mmol, 56.6%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:39][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:16])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NCCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCc1ccccc1)O2
Yield: 62.2 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 356 mg CDI (2.20 mmol) and 266 mg phenethylamine (2.2 mmol) produced 440 mg of 6-hydroxy-2,5,7,8-tetramethyl-N-phenethylchroman-2-carboxamide as a clear pale brown oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[OH:23][C:24]1[CH:25]=[C:26]([O:33][CH:34]([CH3:36])[CH3:35])[CH:27]=[C:28]([CH:32]=1)[C:29](O)=[O:30].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[OH:23][C:24]1[CH:25]=[C:26]([O:33][CH:34]([CH3:36])[CH3:35])[CH:27]=[C:28]([CH:32]=1)[C:29]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:30]
Reactant: Nc1nccs1
Reactant: CC(C)Oc1cc(O)cc(C(=O)O)c1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 53.3 %

Procedure:
After adding 2.45 g (24.5 mmol) of 2-aminothiazole, 3.40 ml (24.5 mmol) of triethylamine and 4.14 g (24.5 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride to a solution of 2.40 g (12.2 mmol) of the obtained carboxylic acid in chloroform (50 ml) while cooling on ice, the mixture was stirred at room temperature for 13 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, extraction was performed with chloroform, and the organic layer was dried and then concentrated under reduced pressure. After adding 10 ml of 4N aqueous sodium hydroxide to a solution of the obtained residue in methanol (40 ml), the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then saturated aqueous ammonium chloride was added, extraction was performed with chloroform, and the organic layer was dried and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=100:1) to obtain 1.81 g of 5-hydroxy-3-isopropoxy-N-thiazol-2-yl-benzamide (yield: 53%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3cccnc3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[C:31]3[C:19](=[CH:20][C:21]4[N:22]([CH2:32][CH3:33])[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=5[C:29]=4[CH:30]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11]=2[CH:12]=1)(=O)=O.[C:36]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:41]=[CH:40][C:39]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:45][CH:44]=2)=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:46]1([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:45]=[CH:44][C:43]([N:42]([C:39]2[CH:40]=[CH:41][C:36]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[CH:37][CH:38]=2)[C:7]2[CH:8]=[CH:9][C:10]3[C:31]4[C:19](=[CH:20][C:21]5[N:22]([CH2:32][CH3:33])[C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=6[C:29]=5[CH:30]=4)[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:11]=3[CH:12]=2)=[CH:48][CH:47]=1
Reactant: c1ccc(-c2ccc(Nc3ccc(-c4ccccc4)cc3)cc2)cc1
Reactant: CCn1c2ccccc2c2cc3c4ccc(OS(=O)(=O)C(F)(F)F)cc4c4ccccc4c3cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCn1c2ccccc2c2cc3c4ccc(N(c5ccc(-c6ccccc6)cc5)c5ccc(-c6ccccc6)cc5)cc4c4ccccc4c3cc21
Reaction time: 12 h
Yield: 78 %

Procedure:
2.69 g (5.46 mmol) of 10-ethyl-10H-phenanthro[9,10-b]carbazol-3-yl trifluoromethanesulfonate synthesized in Synthetic Example 9, 2.63 g (8.18 mmol) of dibiphenyl-4-ylamine, 0.04 g (0.16 mmol) of Pd(OAc)2, 0.20 g (0.33 mmol) of Binap, and 1.51 g (10.91 mmol) of K2CO3 were put, suspended in 30 ml of toluene, and refluxed and agitated for 12 hours. After the reaction was finished, extraction was performed by dichloromethane, filtering was performed by silica gel, and the column was used at a ratio of hexane:MC=4:1 (v/v) to obtain 2.83 g of N,N-di(biphenyl-4-yl)-10-ethyl-10H-phenanthro[9,10-b]carbazol-3-amine that was the target compound (yield 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[C:6]([Cl:16])[C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[Sn](Cl)Cl.Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH2:19][NH:18]2)[CH:5]=[C:6]([Cl:16])[C:7]=1[S:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(Sc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Product: Cc1ccc(Sc2c(Cl)cc(N3NCC(=O)NC3=O)cc2Cl)cc1

Procedure:
20 g of 2-[3,5-dichloro-4-(4-methylthiophenoxy)phenyl]-1,2,4-triazine-3,5-(2H,4H)-dione were dissolved in 200 ml of hot glacial acetic acid. 25 g of tin(II) chloride.2H2O, followed by 100 ml of concentrated hydrochloric acid, were added, and then the mixture was heated to reflux for four hours. After the mixture had been cooled, the product was filtered off with suction, washed to neutrality with water, and recrystallized from 2-methoxyethanol, melting point 239° C.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CCOC(C)=O.O>[Cl:24][C:2]1[O:1][C:5]([C:6]2[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: N#Cc1ccc(-c2cnco2)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(-c2cnc(Cl)o2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of 4-Oxazol-5-yl-benzonitrile (3 g, 17.65 mmol) in anhydrous THF (80 mL) at −78° C. under an argon atmosphere was slowly added a solution of LiHMDS (21.2 mL, 1 M in THF, 21.2 mmol). After 1 h at −78° C., solid hexachloroethane (6.275 g, 26.48 mmol) was added. The mixture was then stirred at −78° C. for 1 h and allowed to slowly warm to room temperature and stir for 3 h. The reaction was diluted with AcOEt/H2O (50 mL/15 mL). The organic layer was washed with brine, dried with MgSO4 and filtered. After removal of solvent the solid obtained was recrystallize from Hexane to give the title compound as a white solid (2.95 g, 82%). m.p.=144° C.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:26]2[N:27]=[CH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:8]1)(C)(C)C.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44]O)[CH2:39][CH2:38]1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[C:26]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][CH:14]=[C:13]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:44][CH2:43][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[CH:20]=2)[CH:12]=3)[N:27]=1
Reactant: CN1CCN(CCO)CC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3cccc(O)c3)ccc12
Product: CN1CCN(CCOc2cccc(C#Cc3ccc4c(=NO)cc(-c5cc6ccccc6cn5)oc4c3)c2)CC1

Procedure:
2-Isoquinolin-3-yl-7-{3-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylethynyl}-chromen-4-one oxime was prepared in 9% overall yield using the method described in examples 44 and 44A, starting from 7-(3-hydroxyphenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (tert-butyl protected oxime of example 30) and 2-(4-methyl-piperazin-1-yl)-ethanol. The title compound was isolated as a yellow solid and as a 90/10 mixture of Z/E oxime isomers after Preparative HPLC purification (gradient 65-50% Water/acetonitrile+0.05% trifluoroacetic acid).