Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][CH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C>C(O)C>[C@H:21]1([NH:20][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NC1CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 20 h
Yield: 59.7 %

Procedure:
For 20 hours, 1.83 g 6-chloropurine riboside, 0.95 g (R) (-)-1-aminoindane and 0.862 g triethylamine are refluxed in 50 ml absolute ethanol under nitrogen atmosphere. The solvent is evaporated to dryness and residue is treated with 50 ml cold water. The solid material is filtered, dissolved in excess ethanol, and volatiles are evaporated under reduced pressure to remove water. Residue upon treatment with ethanol affords solid material. It is filtered and dried. One more crop of the same material is obtained from the mother liquor yielding 1.46 g (60% of theory) of N(6) [1-(R)-indanyl]adenosine having a melting point of 185°-187° C.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]2[CH:11]=[CH:12][C:13]([O:15]C(OC)=O)=[CH:14][C:4]=2[S:3]1.[OH-].[K+]>C(O)(=O)C>[OH:15][C:13]1[CH:12]=[CH:11][C:5]2[N:6]([C:7]([O:9][CH3:10])=[O:8])[C:2](=[NH:1])[S:3][C:4]=2[CH:14]=1
Reactant: COC(=O)Oc1ccc2c(c1)sc(=N)n2C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)n1c(=N)sc2cc(O)ccc21
Temperature: 20 °C
Reaction time: 5 h
Yield: 35.6 %

Procedure:
956 mg of methyl 2-imino-6-[(methoxycarbonyl)oxy]-1,3-benzothiazole-3(2H)-carboxylate are placed in 38 cm3 of aqueous 5N potassium hydroxide solution in a three-necked flask. The solution is stirred at a temperature in the region of 20° C. for 5 hours. The reaction medium is placed in a bath at 0° C., and acetic acid is then added dropwise to pH 5-6. The precipitate is filtered off by suction and then washed with twice 5 cm3 of water. The solid is taken up in 10 cm3 of water, stirred for two hours and then filtered off by suction, washed with twice 2 cm3 of water and dried under a stream of air. 270 mg of methyl 6-hydroxy-2-imino-1,3-benzothiazole-3(2H)-carboxylate are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[NH:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=2)=[S:28])=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Nc2ccc3ccccc3n2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Nc3ccc4ccccc4n3)cc2)ccc1Cl
Yield: 0.1 %

Procedure:
2-(4-aminophenylamino)quinoline (5.0 moles, 1.15 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (5.0 moles, 1.20 g) were reacted according to procedure C of to yield the title compound 1.60 g, 68%. Mass Spec (FD) 473. Calculated for C23H16C1F3N4S: C,; H,; N, Found: C,; H,; N,.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[S:26][C:25]([C:27](O)=[O:28])=[N:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:25]3[S:26][C:22]([CH3:21])=[CH:23][N:24]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)s1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1cnc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)s1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-2-thiazolecarboxylic acid, as starting materials, MS (LC/MS): 428.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][CH:13]([CH3:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=S)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[N:12][CH:13]([CH3:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(NC(=S)Nc1cc(Cl)cc(Cl)c1)C(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(N=C=Nc1cc(Cl)cc(Cl)c1)C(C)(C)C

Procedure:
To a solution of 2.5 g of N-(3,5-dichlorophenyl)-N'-(1,2,2-trimethylpropyl)thiourea produced in Example A-6 in 50 ml of THF were added 2.2 g of DCC and 0.36 g of triethylamine. The mixture was refluxed for 4 hours and evaporated in vacuo. The residue was extracted with petroleum ether. The extract was evaporated in vacuo to give N-(3,5-dichlorophenyl)-N'-(1,2,2-trimethylpropyl)carbodiimide as an oil. To a solution of this oil in 20 ml of THF were added 1.0 g of cyanamide and 1 ml of diisopropylethylamine. The mixture was refluxed for 40 hours and evaporated in vacuo. The residue was recrystallized from benzene to give 1.2 g of the title compound as colorless needles melting at 154.0°-156.0° C.
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([CH3:19])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:18])[CH2:16][CH3:17])(=O)=O)=CC=1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]2[CH2:26][CH2:27][O:28][C:24]=2[CH:23]=1>>[CH3:19][CH:11]([O:21][C:22]1[CH:30]=[CH:29][C:25]2[CH2:26][CH2:27][O:28][C:24]=2[CH:23]=1)[CH2:12][CH2:13][CH:14]=[C:15]([CH3:18])[CH2:16][CH3:17]
Reactant: Oc1ccc2c(c1)OCC2
Reactant: CCC(C)=CCCC(C)OS(=O)(=O)c1ccc(C)cc1
Product: CCC(C)=CCCC(C)Oc1ccc2c(c1)OCC2

Procedure:
1,5-dimethyl-4-heptenyl p-toluenesulfonate and 6-hydroxy-2,3-dihydrobenzofuran are reacted to produce 6-[(1,5-dimethyl-4-heptenyl)-oxy]-2,3-dihydrobenzofuran of boiling point (bulb-tube) 120° C./0.02 mmHg; nD20 = 1.5226; and
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH2:20][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:8]=3[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]4)[CH2:2][CH2:3]2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1cccc2ccccc12
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(Cc4cccc5ccccc45)CC3)cccc2n1
Yield: 58 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 1-(chloromethyl)naphthalene (65.4 mg; 0.37 mmol) to obtain 44.7 mg. (58% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.0 (br s, 1H), 8.95 (br s, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.92 (m, 2H), 7.69 (m, 1H), 7.55 (m, 1H), 7.49 (m, 5H), 7.23 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 3.99 (s, 2H), 3.0 (m, 6H), 2.38 (m, 2H). ESIMS+385.7 m/z
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Cl[C:18]1[C:23]2[N:24]=[CH:25][S:26][C:22]=2[CH:21]=[CH:20][CH:19]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].[Pd].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>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[C:23]3[N:24]=[CH:25][S:26][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[CH:3][CH:4]=1)[C:13]([F:16])([F:15])[F:14]
Reactant: Clc1cccc2scnc12
Reactant: FC(F)(F)C(c1ccc(Br)cc1)C(F)(F)F
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: FC(F)(F)C(c1ccc(-c2cccc3scnc23)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
a 500 mL 2-neck round-bottomed flask was equipped with a reflux condenser and replaced by nitrogen. 70 mL of THF that was dried with 0.11 mol of Mg metal was added to the above flask and then, 0.10 mol of 1-bromo-4-(1,1,1,3,3,3-hexafluoropropane-2-yl)benzene was added in a dropwise fashion. The reaction was significantly exodermic and thus a cooling bath was equipped to reduce the temperature inside the reactor less than 50° C. It was agitated for 2 hours at room temperature, 0.11 mol of zinc chloride was added with 100 mL of THF, and further agitated for 2 hours to obtain a slurry-phase reaction mixture. Another flask was replaced by nitrogen and then 0.10 mol of 4-chlorobenzothiazole derivative, 0.10 mol of Pd, and 3 mol % of Pd(PPh3)4 were dissolved in 100 mL of THF. The prepared solution was added to the reaction mixture and then agitated 60° C. for 24 hours. After the reaction is complete, the resulting product was placed on a silica gel column to remove an inorganic slurry, and then a THF solution was concentrated under vacuum to obtain 4-(4-(1,1,1,3,3,3-hexafluoropropane-2-yl)phenyl)benzo[d]thiazole using column chromatography at a yield of 91%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]SC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:22])[C@H:9]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Reactant: CSC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](c1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To (R)-methyl 2-(tert-butoxycarbonylamino)-2-phenylacetate (E4) in DMF at −40° C. was added NaH and the solution was warmed to 0° C. for 20 minutes. DMS was added and solution was stirred at room temperature for 3 hours. The mixture was poured into NH4Cl(sat)/HCl (1N) 3:1 and extracted with EtOAc. The organics were dried (Na2SO4), filtered and evaporated to give crude E5. Column chromatography Hexanes/EtOAc gave pure (R)-methyl 2-(tert-butoxycarbonyl (methyl)amino)-2-phenylacetate (E5).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][CH:20]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:33][CH3:34].C[N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C>[C:26]([C:25]1[CH:29]=[CH:30][C:22]([CH:20]2[O:19][N:18]=[C:17]([C:12]3[N:13]=[C:14]([CH3:16])[N:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:31]=[CH:32][C:2]([F:1])=[C:3]([O:33][CH3:34])[CH:4]=4)=[O:9])[CH:11]=3)[CH2:21]2)=[CH:23][CH:24]=1)(=[O:28])[NH2:36]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccc(C(=O)O)cc4)C3)nc(C)n2)ccc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccc(C(N)=O)cc4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
To a stirred solution of 4-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)benzoic acid (0.1 g, 0.215 mmol) in DMF (10 mL) was added HATU (0.123 g, 0.323 mmol) and DIEA (0.055 g, 0.43 mmol). The reaction mixture was stirred at RT for about 10 min. Ammonia solution (3 mL) was added and the reaction mixture stirred for about another 2 h. The reaction mixture was diluted with ice cold water (20 mL). The solid which was obtained was filtered, washed with water and dried under vacuum to afford 6-(5-(4-carbamoylphenyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.05 g), (50%) as an off white solid. LC/MS (Table 1, Method c) R1=4.48 min. MS m/z: 464.2 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1([CH3:40])[CH:18]([C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[N:17]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:16]2[S:15][CH2:14]1>C(Cl)(Cl)Cl>[Br:12][C:13]1([CH3:40])[CH:18]([C:19]([O:21][CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])=[O:20])[N:17]2[C:27](=[O:39])[CH:28]([NH:29][C:30](=[O:38])[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:16]2[S:15](=[O:9])[CH2:14]1
Reactant: CC1(Br)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC1(Br)CS(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Yield: 88.3 %

Procedure:
A solution of m-chloroperbenzoic acid (0.445 g) in chloroform (5 ml) was added to a solution of 2,2,2-trichloroethyl 3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (1.21 g) under stirring at -5° to -10° C., and the mixture was stirred for an hour at the same temperature. After the reaction, the reaction mixture was washed with 5% sodium bicarbonate aqueous solution and with water in turn and then dried. After the solvent was distilled off, the residue was crystallized by adding ether. Thus obtained crystals were recrystallized from ethanol to give 2,2,2-trichloroethyl 3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate-1-oxide (1.10 g), mp 159° to 161° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10](O)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O.C(=O)([O-])O.[Na+]>>[Cl:24][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(O)nc1C(C)C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(Cl)nc1C(C)C
Temperature: 103 °C
Yield: 97.3 %

Procedure:
In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.00 g (3.43 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine and 3.4 mL (3.7 mmol.) of phosphorus oxychloride. The mixture was heated to 100-106° C. for 1.5 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, and poured into an ice/water mixture. The resulting aqueous mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution. The neutralized aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure, to obtain 1.03 g of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product having the below-mentioned characteristics. The yield was 97% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: CC([O-])(C)C.[Na+].Br[C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.[C:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])[CH2:23][CH3:24]>CC([O-])=O.CC([O-])=O.[Pd+2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CCCCCC.CCOC(C)=O>[C:12]([C:11]1[CH:20]=[CH:21][C:8]([CH:23]([CH3:24])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])=[CH:9][CH:10]=1)(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCC(=O)c1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C(=O)c1ccccc1)c1ccc(C(=O)c2ccccc2)cc1
Yield: 96.7 %

Procedure:
Pd(OAc)2 (4.5 mg, 0.020 mmol), Tri-t-butylphosphine (4.1 mg, 0.020 mmol), NaOtBu (144 mg, 1.50 mmol), 4-Bromobenzophenone (261 mg, 1.00 mmol) and Propiophenone (148 mg, 1.10 mmol) were used. Reaction at 70° C. for 12 h gave 304 mg (97%) of 2-(4-Benzoylphenyl)-1-phenyl-1-propanone after silica gel chromatography (hexane/EtOAc=85/15). 1H NMR: (CDCl3) δ 7.96 (d, J=7.7 Hz, 2H) , 7.76-7.75 (m, 4H), 7.58 (t, J=7.2 Hz, 1H), 7.52 (t, J=7.1 Hz, 1H), 7.47 (t, J=7.7 Hz, 2H), 7.43-7.40 (m, 4H), 4.79 (q, J=6.9 Hz, 1H), 1.59 (d, J=6.9 Hz, 3H); 13C{1H} NMR: (CDCl3) δ 199.66, 196.14, 146.16, 137.51, 136.23, 133.10, 132.40, 130.82, 129.94, 129.80, 128.75, 128.63, 128.26, 127.79, 47.72, 19.37. MS m/e (relative intensity): 314 (10), 105 (100), 77 (38), 51 (13). Anal. Calcd for C22H18O2 : C, 84.05; H, 5.77. Found: C, 83.91: H, 5.88.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)[N:3]=1.[C:15]1([CH:22]=[CH:21][CH:20]=[C:18]([OH:19])[CH:17]=1)[OH:16].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C(C)=CC=CC=1>[OH:16][C:15]1[CH:17]=[C:18]([OH:19])[CH:20]=[CH:21][C:22]=1[C:2]1[N:7]=[C:6]([C:20]2[CH:21]=[CH:22][C:15]([OH:16])=[CH:17][C:18]=2[OH:19])[N:5]=[C:4]([C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: Oc1cccc(O)c1
Reactant: Cn1cccc1-c1nc(Cl)nc(Cl)n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: Cn1cccc1-c1nc(-c2ccc(O)cc2O)nc(-c2ccc(O)cc2O)n1
Yield: 81 %

Procedure:
Friedel-Crafts acylation: In a 500 ml sulfonation flask having a stirrer, dropping funnel, condenser and internal thermometer, 22.9 g (0.1 mol) of 2,4-dichloro-6-(1-methylpyrrol-2-yl)-1,3,5-triazine and 24.2 g (0.22 mol) of resorcinol are initially introduced into 200 ml of xylene (isomer mixture). At 45-50° C., 29.3 g (0.22 mol) of aluminium chloride are slowly introduced and the mixture is stirred at 80-83° C. until the evolution of HCl has ended (about 2 hours). The warm reaction solution is allowed to run into dil. hydrochloric acid with stirring, and the solid is filtered off with suction and washed with acetone/water until neutral. Drying is carried out at 100° C. in vacuo. 30.5 g (81.0% of theory) of 2,4-bis(2,4-dihydroxyphenyl)-6-(1-methylpyrrol-2-yl)-1,3,5-triazine are obtained as a yellow powder (m.p.>300° C.). The structure is in agreement with the 1H-NMR spectrum.
Reaction SMILES: [CH3:1][C:2]1[N:3]=NNN=1.[CH:7]1([C:10]2[N:11]=[N:12][NH:13][N:14]=2)[CH2:9][CH2:8]1>>[CH:7]1([C:10]2[N:11]=[N:12][N:13]([CH2:1][CH2:2][NH2:3])[N:14]=2)[CH2:9][CH2:8]1
Reactant: Cc1nn[nH]n1
Reactant: C1CC1c1nn[nH]n1
Product: NCCn1nnc(C2CC2)n1

Procedure:
This compound is prepared by an analogous procedure to intermediate CK1 by replacing 5-Methyl-2H-tetrazole in step 1 with 5-Cyclopropyl-2H-tetrazole.
Reaction SMILES: FC1C([O:8][C:9]([C:11]2[C:29]([F:30])=[C:28]([F:31])[C:14]3[N:15]([C:20]4[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=4[CH3:27])[CH2:16][O:17][C:18](=[O:19])[C:13]=3[CH:12]=2)=O)=C(F)C(F)=C(F)C=1F.C1COCC1.Cl.CN.[CH:44]([N:47](CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:44][NH:47][C:9]([C:11]1[C:29]([F:30])=[C:28]([F:31])[C:14]2[N:15]([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[CH3:27])[CH2:16][O:17][C:18](=[O:19])[C:13]=2[CH:12]=1)=[O:8]
Reactant: Cc1cc(I)ccc1N1COC(=O)c2cc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c(F)c21
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc2c(c(F)c1F)N(c1ccc(I)cc1C)COC2=O
Reaction time: 17 h
Yield: 76.8 %

Procedure:
To a suspension of 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid (0.3 g, 0.67 mmol) in N,N-dimethylformamide (3 mL) is added trifluoroacetic acid pentafluorophenyl ester (0.127 mL, 0.74 mmol) and pyridine (0.60 mL, 0.74 mmol). After stirring for 4 hours the reaction mixture is diluted with ethyl acetate and washed 3 times with 1.0 M HCl solution, 3 times with 5% aqueous NaHCO3 solution, 2 times with water and once with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid pentafluorophenylester as a dark orange oil (0.34 g, 83.1%). To a suspension of 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid pentafluorophenylester (0.33 g, 0.54 mmol) in freshly distilled THF (10 mL) is added methylamine hydrochloride (0.037 g, 0.54 mmol) and N,N-diisopropylethylamine (0.019 mL, 1.08 mmol). After stirring for 17 hours, the reaction mixture was diluted with ethyl acetate and washed 2 times with water and 2 times with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid methylamide as a yellow solid (0.19 g, 76.9%); mp 219–223° C.; 1NMR (400 MHz; DMSO-d6) 8.40 (s, 1H), 8.06 (d, 1H, J=6.8), 7.74 (s, 1H), 7.50 (d, 1H, J=8.4), 6.87 (d, 1H, J=8.0), 5.61 (s, 2H), 2.76 (d, 3H, J=4.4), 2.25 (s, 3H); MS(APCI)m+1=459; Anal.calcd/found for C17H13F2IN2O3 C 45.00/45.39, H 3.01/3.16, N 6.05/5.88.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:4]=1.[H][H]>CO.Cl.[Pt]=O>[ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:4]=1
Reactant: [H][H]
Reactant: NC1=NC(c2ccncc2)Cc2ccccc21
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: NC1=NC(C2CCNCC2)Cc2ccccc21
Yield: 82 %

Procedure:
A slurry of platinum oxide (8 mg, 10 moll) in methanol (1 ml) was added to a solution of 1-amino-3-(4-pyridyl)-3,4-dihydroisoquinoline hydrochloride (Example 28) (150 mg, 0.578 mmol) in methanol and concentrated hydrochloric acid (0.4 ml), and stirred under 3 atmospheres of hydrogen for 16 h. The mixture was filtered through celite and evaporated. The residue was purified by RP-HPLC to yield a white hygroscope solid (126 mg). [M+H]+ 230; 360 MHz 1H n.m.r (d6 -DMSO) 10.30 (1H, s), 9.43 (1H, s), 9.03 (1H, s), 8.80 (1H, br.s), 8.56 (1H, br.s), 8.05 (1H, d, J 7.8 Hz), 7.71 (1H, t, J 7.5 Hz), 7.54-7.50 (2H, m), 3.72-3.68 (1H, m), 3.27 (2H, d, J 13.2 Hz), 3.15 (1H, dd, J 17, 4 Hz), 2.99 (1H, dd, J 17.2, 6.9 Hz), 2.80-2.74 (2H, m), 1.95-1.63 (3H, m), 1.48-1.38 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCNCC3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 3E (900 mg, 2.120 mmol) in 10 mL dicholoromethane was added trifluoroacetic acid (1.634 mL, 21.2 mmol). The mixture was stirred at room temperature for 2 hours and the solvent was removed by azeotroping with ethyl acetate. The residue was dissolved in 3 mL methanol and treated with 2M hydrogen chloride in ether (1 mL) for 1 hour. The mixture was diluted with ether and the solid filtered to give the title compound as a hydrochloride salt. 1H NMR (300 MHz, DMSO-d6) δ 2.64-2.81 (m, 2H) 3.76-3.82 (m, 3H) 3.81-3.90 (m, 2H) 6.52 (s, 1H) 6.56 (s, 1H) 7.17-7.33 (m, 1H) 7.32-7.49 (m, 2H) 8.86 (s, 1H) 8.95 (s, 2H) 12.57 (s, 1H). MS (ESI+) m/z 325.1 (M+H)+.