Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[C:12](Cl)=[N:13][C:14]([CH3:17])=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH2:20][OH:21]>O1CCCC1>[CH2:3]([O:10][C:11]1[C:12]([O:21][CH2:20][C:19]([O:23][CH3:24])=[O:22])=[N:13][C:14]([CH3:17])=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ncc(OCc2ccccc2)c(Cl)n1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COc1nc(C)ncc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
68 mg of sodium hydride was added to a mixture of 0.4 g of 5-benzyloxy-4-chloro-2-methylpyrimidine, 0.17 g of methyl glycolate and 3.4 ml of tetrahydrofuran at 0° C. The mixture was stirred at room temperature for 1 hour, then, the reaction solution was stirred for 30 minutes at 90° C. 18 mg of methyl glycolate was additionally added to this, and the mixture was stirred for 30 minutes at 90° C. The reaction solution was cooled to room temperature, then, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.21 g of 5-benzyloxy-4-(methoxycarbonyl)methoxy-2-methylpyrimidine.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=O.[CH3:9][NH:10][C:11](=[S:14])[NH:12][NH2:13].C(=O)(O)[O-].[Na+].Cl>C(OCC)(=O)C.N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([CH3:9])[C:11]([SH:14])=[N:12][N:13]=1
Reactant: CNC(=S)NN
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cn1c(S)nnc1-c1ccco1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Furoyl chloride (0.76 ml, 7.66 mmol) was added in a dropwise manner to a solution of 4-methyl-3-thiosemicarbazide (732 mg, 6.96 mmol) and pyridine (7 ml) and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate (100 ml), successively washed with water (3×100 ml) and brine (100 ml). The organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo. The residue was suspended in sodium bicarbonate (70 ml, 69.6 mmol, 1 M water) and left stirring at 100° C. overnight. The reaction mixture was cooled to 0° C., then brought to pH about 6 using hydrochloric acid (70 ml, 1 N water). The title compound (298 mg) was collected by filtration as a white solid. 1H NMR (CDCl3), δ (ppm): 11.4 (bs, 1H), 7.63 (d, 1H), 7.02 (d, 1H), 6.60 (dd, 1H), 3.83 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[N:14]3[CH:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]3=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[N:11]=2)[CH2:6][CH2:5]1.[CH3:33]NC>>[CH3:1][N:2]([CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:14]3[CH:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]3=[C:12]([C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:24][CH:25]=3)[N:11]=2)[CH2:6][CH2:5]1)[CH3:33]
Reactant: CNC[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)CC1
Reactant: CNC
Product: CN(C)CC1CCC(c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn23)CC1

Procedure:
Prepared according to the procedure described above for the synthesis of trans-3-(4-methylaminomethyl-cyclohexyl)-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-8-ylamine, except using dimethyl-amine.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC([O-])=O.[Na+].[NH:18]([CH3:20])[CH3:19].Cl.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:19][N:18]([CH3:20])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)Cc1cccc2ccccc12
Reaction time: 12 h
Yield: 92 %

Procedure:
To 1-naphthaldehyde (1.50 g, 9.62 mmol, 1.00 equiv) in 40 mL THF is added NaOAc (0.79 g, 9.62 mmol, 1.00 equiv), Me2NH.HCl (863 mg, 10.6 mmol, 1.10 equiv), and AcOH (0.11 mL, 1.9 mmol, 0.20 equiv) at 23° C. NaBH(OAc)3 (4.08 g, 19.3 mmol, 2.00 equiv) is added in three portions over five minutes. The suspension is stirred for 12 hours before solvent is removed in vacuo. To the residue is added 10 mL sat. NaHCO3(aq) and 10 mL CH2Cl2. The phases are separated and the aqueous phase is extracted with CH2Cl2 (3×10 mL). The combined organic phase is concentrated in vacuo. The residue is purified by chromatography on silica gel eluting with hexanes/EtOAc 3:2 (v/v) to afford 1.64 g of the title compound as a colorless liquid (92% yield).
Reaction SMILES: [CH3:1][C:2]1[O:8][C:7]([CH3:9])=[CH:6][C:4](=[O:5])[CH:3]=1.[H][H]>CO.[Pd]>[CH3:9][C@H:7]1[CH2:6][C:4](=[O:5])[CH2:3][C@@H:2]([CH3:1])[O:8]1
Reactant: [H][H]
Reactant: Cc1cc(=O)cc(C)o1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CC(=O)C[C@H](C)O1
Yield: 88 %

Procedure:
10 g of 2,6-dimethyl-gamma-pyrone are dissolved in 200 ml of methanol and then 0.8 g of palladium-on-charcoal at 10% is added. The reaction mixture is stirred for 24 hours under 25 atmospheres of hydrogen. The medium is filtered and then the solvent is evaporated off. 8.81 g of cis-2,6-dimethyltetrahydro-pyran-4-one are recovered. Yield=88%.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1.[BH4-].[K+].[Cl-].[Li+].O>C1COCC1>[OH:2][CH2:3][C:4]1[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[N:6][C:7]([CH3:10])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C)nc1Nc1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CO)c(Nc2cccc([N+](=O)[O-])c2)n1
Yield: 88.5 %

Procedure:
To a solution of 6-methyl-2-(3-nitrophenylamino)nicotinic acid methyl ester (13.84 g, 48.18 mmol) in THF (180 ml) was added potassium borohydride (3.12 g, 57.82 mmol) and lithium chloride (2.45 g, 58.82 mmol) and the mixture was heated under reflux. Potassium borohydride (0.52 g, 9.64 mmol) was added three times at one hour intervals and the mixture was further heated under reflux for 1 hour. Evaporation of the solvent under reduced pressure gave a residue which was admixed with water to form crystals. The crystals were collected by filtration, washed successively with water and isopropanol, and dried to give 3-hydroxymethyl-6-methyl-2-(3-nitrophenylamino)-pyridine (11.05 g, 88%).
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][N:4]=1.Br[CH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:18]([C:22]([F:25])([F:24])[F:23])[O:19]2)=[CH:14][C:13]=1[Cl:31]>[Cl-].[Cl-].[Zn+2].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.C1COCC1>[Cl:31][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[CH2:11][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][N:4]=1)[O:19][CH:18]([C:22]([F:25])([F:24])[F:23])[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16]2
Reactant: Cc1ccc([Mg]Br)nc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(Cl)c(Cc3ccc(C)cn3)cc2OC1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 14.6 %

Procedure:
The bromo (5-methylpyridin-2-yl)magnesium (10.4 mL, 2.6 mmole) was diluted by 5 mL THF under nitrogen and the solution was cooled to −78° C. ZnCl2 (340 mg, 2.5 mmole) was added to above solution and the mixture was stirred for 0.5 hr. The ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 16, Step 3 (01597/1 PR) (1.0 g, 2.5 mmol) was added to above mixture and followed by PdCl2(PPh3)2 (18 mg, 0.025 mmole). The mixture was warmed to room temperature and heated to 50° C. for 3 hr. LCMS indicated that the product was formed around 15%. The solid was filtered off and the filtrate was concentrated to give a crude mixture, which was purified by RPHPLC eluted with 10 to 95% ACN in water with 0.05% TFA to afford 150 mg the desired product as a brown oil (yield 15%), which had suitable purity to use without further purification.
Reaction SMILES: ClC(Cl)C.S(Cl)(Cl)=O.[CH3:9][C:10]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[N:24][O:25][CH3:26])[C:21]([OH:23])=O.O[N:33]=[C:34]([NH2:37])[CH2:35][CH3:36]>CCOCC.N1C=CC=CC=1.CN(C)C=O>[CH3:26][O:25][N:24]=[C:20]([C:21]1[O:23][N:37]=[C:34]([CH2:35][CH3:36])[N:33]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][O:12][C:11]1[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:10]=1[CH3:9]
Reactant: CCC(N)=NO
Reactant: CON=C(C(=O)O)c1ccccc1COc1cc(C)ccc1C
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCc1noc(C(=NOC)c2ccccc2COc2cc(C)ccc2C)n1
Yield: 34.5 %

Procedure:
Dichloroethane (5 ml), thionyl chloride (0.65 g, 5.5 mmol) and N,N-dimethylformamide (0.05 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetic acid (1.57 g, 5 mmol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, pyridine (3 ml) and 1-hydroxyimino-1-propylamine (0.88 g, 10 mmol) were added to the residue, and the mixture was stirred under reflux for 0.5 hours. After completion of the reaction, ether (150 ml) was added, and the mixture was washed with 1N hydrochloric acid (150 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 3-ethyl-1,2,4-oxadiazol-5-yl ketone O-methyloxime (0.63 g, 34.5%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:29])=[C:20]([NH:22][S:23]([CH:26]3[CH2:28][CH2:27]3)(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH2:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34]>>[F:29][C:19]1[CH:18]=[CH:17][C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[N:7]=2)=[CH:21][C:20]=1[NH:22][S:23]([CH:26]1[CH2:28][CH2:27]1)(=[O:25])=[O:24]
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(Cl)n2)s1
Reactant: CS(=O)(=O)CCN
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)C3CC3)c2)c(-c2ccnc(NCCS(C)(=O)=O)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}cyclopropanesulfonamide (80 mg, 0.177 mmol) and 2-aminoethyl-methyl-sulfone (174 mg, 1.413 mmol) the title compound was obtained as a white solid (49 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.70 (s, 1H), 8.13 (d, J=4.8 Hz, 1H), 7.50 (dd, J=7.6, 1.6 Hz, 1H), 7.44 (t, J=4.9 Hz, 1H), 7.25-7.41 (m, 2H), 6.33 (d, J=4.5 Hz, 1H), 3.62 (d, J=5.5 Hz, 2H), 3.32 (br. s., 2H), 3.22-3.27 (m, 1H), 2.97 (s, 3H), 2.52-2.68 (m, 1H), 1.33 (d, J=6.9 Hz, 6H), 0.71-0.96 (m, 4H). MS (ESI): 540.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([CH:17]=[O:18])[C:11]2=[CH:10][C:9]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.[C-]#N.[Na+].[CH3:35][OH:36]>[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([C:17]([O:36][CH3:35])=[O:18])[C:11]2=[CH:10][C:9]=1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1
Reactant: CO
Reactant: CC(C)(C)C(=O)c1oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc2c1C=O
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Product: COC(=O)c1c(C(=O)C(C)(C)C)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 10 mL rb flask equipped with a magnetic stir bar and a septum was charged with a solution of 50 mg (0.11 mmol) of the product of Example 90, in 2 mL MeOH, 24 mg (0.27 mmol) of manganese dioxide and ca. 5 mg of sodium cyanide was added. The reaction mixture was stirred at room temperature for 4 h, then filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 0–10% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 482.2 (M+1), 484.0 (M+3); Rt=4.57 min.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]3[N:19]=[CH:20][N:21]=[C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([Cl:31])[CH:25]=4)[C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pt]=O>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:22]2[C:17]3[CH:16]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:25][C:26]=1[Cl:31]
Reactant: [H][H]
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(-c2ccc(O)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Yield: 48.9 %

Procedure:
After dissolving 255 mg of the 4-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-2-chlorophenylamine synthesized in Production Example 153-5 in 10 ml of ethanol and 3 ml of tetrahydrofuran, 100 mg of platinum oxide was added and the mixture was stirred overnight at room temperature under normal pressure in a hydrogen atmosphere. After filtering with celite, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 105 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH2:4]Br.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH2:4][C:3]2[C:2]([F:1])=[C:9]([F:10])[CH:8]=[CH:7][C:6]=2[F:11])=[CH:15][CH:14]=1
Reactant: Fc1ccc(F)c(CBr)c1F
Reactant: Sc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Fc1ccc(F)c(CSc2ccc(Cl)cc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
2,3,6-Trifluorobenzyl bromide (9.79 g, 43.3 mmol) and 4-chlorothiophenol (6.23 g, 43.3 mmol) were dissolved in 300 mL of THF. Triethylamine (4.59 g, 45.4 mmol) was added. The solution was stirred at room temperature overnight. 300 mL of EtOAc and 300 mL of water were added. The organic layers were washed with 200 mL 1N HCl solution, dried over Na2SO4 and concentrated. The residue was pure product (12.5 g, quant. yield). 1H NMR (CDCl3 400 MHz) δ 7.30 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H), 7.03 (m, 1H), 6.77 (m, 1H), 4.08 (s, 2H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([CH3:16])[N:6]=1)([CH3:3])[CH3:2].[Cl:17][C:18]1[C:23]([C:24](O)=[O:25])=[C:22]([F:27])[C:21]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:20][CH:19]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:17][C:18]1[C:23]([C:24]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[C:7]([CH3:16])[N:6]=[C:5]3[NH:4][CH:1]([CH3:3])[CH3:2])=[O:25])=[C:22]([F:27])[C:21]([CH2:28][NH:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:20][CH:19]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Cc1nc(NC(C)C)c2cccc(N)c2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(NC(C)C)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 33.8 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-isopropyl-2-methylquinazoline-4,8-diamine (Intermediate-50, 30 mg, 0.14 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 60 mg, 0.20 mmol), oxalyl chloride (38 mg, 0.30 mmol), DMF (1 drop) and DIPEA (77 mg, 0.60 mmol) in CH2Cl2 (2 mL) to afford 23 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 8.65 (d, J=7.6 Hz, 1H), 8.12-8.01 (t, J=8.4 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.43 (d, J=7.7 Hz, 1H), 7.41-7.35 (m, 3H), 4.57-4.52 (m, 1H), 4.30 (d, J=5.6 Hz, 2H), 2.44 (s, 3H), 1.25 (s, 3H), 1.24 (s, 3H), 1.13 (s, 9H); MS (m/z): 486.27 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40](B(O)O)=[C:39]2[C:34]=1[CH:35]=[CH:36][CH:37]=[CH:38]2.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:40]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:11]4[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[C:39]2[C:34]=1[CH:35]=[CH:36][CH:37]=[CH:38]2
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: OB(O)c1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-n2c(-c3ccc(-c4c5ccccc5c(-c5ccc6ccccc6c5)c5ccccc45)cc3)nc3ccccc32)cc1
Yield: 81 %

Procedure:
Dissolving 4.0 g (11 mmol) of 2-(4-bromophenyl)-1-phenyl-1H-benzimidazole, 4.0 g (11 mmol) of 10-naphthalene-2-yl-anthracene-9-boronic acid and 0.27 g of tetrakis (triphenylphosphine) palladium into 40 milliliter of 1,2-dimethoxyethane, adding 18 milliliter of 2.0M sodium carbonate aqueous solution, the resultant suspension was refluxed with heating for 7 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and methanol, thereby obtaining 5.1 g of yellowish white solids (yield: 78%). As a result of mass spectrum (MS) analysis, it was recognized that the yellowish white solids were identified as the aimed substance and that m/e=572 for molecular weight of 572.23.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37].[CH3:38][CH:39]([NH:41][CH2:42][CH2:43][CH2:44][NH2:45])[CH3:40]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:45][CH2:44][CH2:43][CH2:42][NH:41][CH:39]([CH3:40])[CH3:38])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:22]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:37]
Reactant: CC(C)NCCCN
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1nc(NCCCNC(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared from 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methyl-N-1,3-thiazol-2-ylbenzamide and N-(1-methylethyl)-1,3-propanediamine by following the procedures in Example 79c. LC-MS m/z 590 (M+H)+; 1H-NMR (MeOD) 1.02 (m, 6 H), 1.68 (m, 2 H), 2.32 (m, 3 H), 2.46 (m, 1 H), 2.66 (m, 1 H), 2.82 (m, 1H), 3.11 (m, 1 H), 3.46 (m, 1 H), 6.35 (d, J=8.8 Hz, 1 H), 7.11 (m, 1 H), 7.24 (m, 2H), 7.46 (m, 2 H), 7.55 (m, 2 H), 8.02 (m, 1 H), 8.11 (d, J=7.6 Hz, 1 H).
Reaction SMILES: COC([C@H]1[C@H]2C[C@@H]3N(C[C@@H]2CC[C@@H]1O)CCC1C2C=CC=CC=2NC3=1)=O.[CH3:27][CH2:28][C@@H:29]1[C@@H:45](/[C:46](/[C:50]([O:52][CH3:53])=[O:51])=[CH:47]/[O:48][CH3:49])[CH2:44][C@@H:43]2[N:31]([CH2:32][CH2:33][C:34]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=4[NH:41][C:42]=32)[CH2:30]1.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:27][CH2:28][C@H:29]1[C@@H:45](/[C:46](/[C:50]([O:52][CH3:53])=[O:51])=[CH:47]/[O:48][CH3:49])[CH2:44][C@@H:43]2[N:31]([CH2:32][CH2:33][C:34]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=4[NH:41][C:42]=32)[CH2:30]1
Reactant: CC[C@H]1CN2CCc3c([nH]c4ccccc34)[C@@H]2C[C@@H]1/C(=C/OC)C(=O)OC
Agent: COC(=O)[C@H]1[C@H]2C[C@H]3c4[nH]c5ccccc5c4CCN3C[C@@H]2CC[C@@H]1O
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC[C@@H]1CN2CCc3c([nH]c4ccccc34)[C@@H]2C[C@@H]1/C(=C/OC)C(=O)OC

Procedure:
The yield amounts to 48.5%, referred to the total amount of corynantheine and dihydrocorynantheine used; m.p. 215°-226° C. (the substance partially sublimes with decomposition above 175° C.); [α]D20 : -25° (c=2; chloroform); IR spectrum (KBr): 1720 (CO), 3365 cm-1 (NH).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C(Cl)Cl.[CH3:25][CH:26]([CH3:44])[CH:27]([C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:43])([F:42])[CH:39]([F:41])[F:40])=[CH:33][CH:32]=1)[C:28](Cl)=[O:29]>CCOCC>[CH:26]([CH:27]([C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:42])([F:43])[CH:39]([F:40])[F:41])=[CH:33][CH:32]=1)[C:28]([O:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)=[O:29])([CH3:44])[CH3:25]
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)(F)C(F)F)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)c1ccc(OC(F)(F)C(F)F)cc1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
To a stirred mixture of 6.81 g (0.0340 mol) of m-phenoxybenzyl alcohol, 3.0 ml (2.95 g, 0.0372 mol) of dried pyridine, and 20 ml of methylene chloride is added over a period of 20 minutes a 20 ml methylene chloride solution of 10.6 g (0.034 mol) of 3-methyl-2-[p-(1,1,2,2-tetrafluoroethoxy)phenyl]butyryl chloride. The reaction mixture is stirred at room temperature for 66 hours and then diluted with 200 ml of ether. The ether solution is washed with 200 ml of 20% hydrochloric acid and 200 ml of water, dried with sodium sulfate, filtered, and then evaporated to give 16.24 g (100%). This product is purified on a silica gel dry column (116 cm×5 cm, eluent=1:1 hexane-methylene chloride) by collecting a sample between 85 cm and 63 cm (solvent front=113 cm) to give 12.60 g (78%) of a clear slightly yellow colored oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([NH2:14])[C:6]([NH2:13])=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:38][C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:21])[NH:13][C:6]4[CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:3]([C:2]([F:15])([F:16])[F:1])=[CH:4][C:5]=4[N:14]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[CH:36][N:35]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: Nc1cc(C(F)(F)F)c(C(F)(F)F)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4,5-bis-trifluoromethyl-benzene-1,2-diamine [CAS-No. 30454-92-3] (244 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) in toluene (10 ml) under reflux conditions for 2 h according to the general procedure M and subsequent treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (304 mg, 66%).