Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([CH:35]=3)[CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.C1COCC1.[OH-].[Li+].Cl>CO>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH3:36])=[C:21]([CH:35]=3)[CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CCN(CCc2cc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)ccc2C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1CCN1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To ethyl 1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl)piperidine-4-carboxylate 52 (0.6 mmol) is added THF (3 mL), MeOH (2 mL) and 3M lithium hydroxide (7.3 mmol). The reaction mixture is stirred at rt for 6 h until complete as detected by LCMS. Subsequently, the organic solvents are evaporated and the reaction mixture is diluted with water (10 mL) then neutralized with 3M HCl (7.3 mmol). The resulting precipitate is filtered, washed with water and air dried. The crude precipitate is purified by preparative LCMS to yield 1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl)piperidine-4-carboxylic acid F2 as white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.69 (s, 1H), 8.79 (s, 2H), 7.75 (d, J=8.0 Hz, 2H), 7.60 (bd, J=8.0 Hz, 1H), 7.56 (bs, 1H), 7.46 (s, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 3.19 (m, 1H), 2.96 (m, 2H), 2.27 (s, 3H), 2.10 (m, 2H), 1.75 (m, 2H). MS (m/z) (M+1)+: 483.2.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][Cl:25].O>CN(C=O)C>[Cl:25][CH2:24][CH2:23][CH2:22][N:11]1[CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:14])[NH:9][C:10]1=[O:13]
Reactant: ClCCCBr
Reactant: O=c1[nH]cc(-c2ccccc2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(=O)n(CCCCl)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-phenyl-2,4(1H,3H)-pyrimidinedione (527 mg, commercially available from Akos) and K2CO3 (386 mg) in dry DMF (10 mL) was stirred for 1 hour at room temperature. 1-Bromo-3-chloropropane (0.28 mL) was added and the mixture was stirred at room temperature for 20 hours. One more portion of 1-bromo-3-chloropropane (0.14 mL) was added and the mixture was stirred at room temperature for 20 hours. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a silica flash chromatography (eluting with A: dichloromethane, B: dichloromethane/methanol=9/1 at ratio A:B=6:4) to give the title compound as a colourless oil (150 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[I:19][C:20]1[N:21]=[CH:22][N:23]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=3)[N:3]=2)[CH:24]=1
Reactant: Ic1c[nH]cn1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.4) (0.27 g, 1.0 mmol) and commercially available 4-iodo-imidazole (0.21 g, 1.1 mmol) according to the general procedure Ia. Obtained as a light brown solid (0.35 g, 81%). MS (ISP) 432.1 [(M+H)+]; mp 193.5° C.
Reaction SMILES: [I-].[CH3:2][N+:3]([CH3:9])([CH3:8])[CH2:4][CH2:5][CH2:6][CH3:7].[OH2:10]>[Ag-]=O>[OH-:10].[CH3:2][N+:3]([CH3:9])([CH3:8])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O
Agent: O=[Ag-]
Agent: CCCC[N+](C)(C)C
Agent: [I-]
Product: [OH-]
Reaction time: 24 h

Procedure:
A typical TMBAOH solution was prepared as follows. Trimethylbutylammonium iodide, 1466.3 g, was dissolved in 1948.6 g deionized water in a 5 liter 3-necked round bottom flask equipped with overhead stirring. A 1 wt. % excess of silver(I) oxide, (99%), 712 g, was added and stirred in the dark for 24 hours. The resulting trimethylbutylammonium hydroxide solution was isolated by filtration.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1>C(#N)C>[S:1]([O:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCc1ccccc1
Solvent: CC#N
Product: NS(=O)(=O)OCCc1ccccc1
Yield: 68 %

Procedure:
The sulfamoyl chloride in acetonitrile solution prepared in (a) was reacted as in Example 12 with 12.2 g (0.1 mole) of β-phenethyl alcohol using 40.4 g (0.4 mole) triethylamine in 100 ml additional acetonitrile followed by using extracting, washing and concentration procedures of Example 12 through the first evaporation. The crude oily residue was purified by chromatography (10×80 cm glass column; 700 g silica gel; eluents methylene chloride followed by 10:1 methylene chloride/acetone). Fractions containing the title compound were combined and solvents evaporated under reduced pressure to give 13.6 g (68% yield) of title compound as light-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:18][C:19]1[N:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:31]([N:28]1[CH2:27][CH2:26][N:25]([C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:15](=[O:17])[CH2:14][C:11]3[CH:12]=[CH:13][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=4)=[N:9][CH:10]=3)=[N:24][CH:23]=2)[CH2:30][CH2:29]1)(=[O:33])[CH3:32]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: O=C(O)Cc1ccc(-c2ccnc(F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(F)c4)nc3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(2′-fluoro-2,4′-bipyridin-5-yl)acetic acid 208-3 (42 mg, 0.18 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (40 mg, 0.18 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 68 mg, 0.18 mmol) were added DMF (1 mL) and diispropylethyl amine (DIEA, 0.15 mL, 0.9 mmol) and the mixture was stirred at room temperature overnight. The crude product, a clear DMF solution, was subjected directly for reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(2′-fluoro-2,4′-bipyridin-5-yl)acetamide 209 as white solid. MS m/z 435.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 10.65 (s, 1H), 8.69 (d, 1H), 8.36 (d, 1H), 8.15 (d, 1H), 8.05-8.02 (m, 2H), 7.94-7.90 (m, 2H), 7.81 (s, 1H), 7.42 (dd, 1H), 3.83 (s, 2H), 3.57-3.54 (m, 4H), 3.15-3.13 (m, 2H), 3.09-3.06 (m, 2H), 2.03 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H][H]>C1CCCCC1>[C:4]1([CH:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)c1ccccc1
Solvent: C1CCCCC1
Product: CC(O)c1ccccc1
Product: CCc1ccccc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 19 %
Yield: 81 %

Procedure:
For Example E15 according to the present invention, the above-described 300 ml autoclave provided with a metal basket fastened to the lid of the autoclave, as used in Example E6 to E12, was employed; in the present example, the metal basket was used for accommodating 9.2 g of the catalyst IC11 (wire mesh rings). In its center, the basket had a cylindrical opening for the shaft of the stirrer, so that the catalyst was supplied uniformly with liquid and gas. The autoclave was charged with 200 ml of cylcohexane and 8 g of acetophenone, closed and freed of air by pressurizing it twice to 100 bar with nitrogen. The autoclave was subsequently heated to 120° C. and 250 bar of hydrogen were injected. While injecting further hydrogen to replace that consumed, the mixture was stirred for a further 60 minutes at this temperature. A total of 1.59 liters of hydrogen were consumed. Analysis of the resulting product by gas chromatography indicated complete conversion of the acetophenone to form 1-phenylethanol (81%) and ethylbenzene (19%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:4]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[N:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH3:47][C:48]1([CH3:55])[O:52][CH:51]([CH2:53][OH:54])[CH2:50][O:49]1.[F-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:47][C:48]1([CH3:55])[O:52][CH:51]([CH2:53][O:54][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][C:9]=3[N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:4]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:3]=2)[CH2:50][O:49]1
Reactant: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)ccnc32)cc1
Reactant: CC1(C)OCC(CO)O1
Agent: [F-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(OCC3COC(C)(C)O3)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)ccnc32)cc1
Temperature: 120 °C
Reaction time: 75 h
Yield: 56.3 %

Procedure:
A mixture of tert-Butyl 4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.12 g, 0.218 mmol, see Example 5), Cu(I)I (0.0416 g, 0.218 mmol), 1,10-phenanthroline (0.0393 g, 0.218 mmol), (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (0.812 mL, 6.55 mmol) and KF on Al2O3 (40%; 0.222 g, 1.53 mmol) in toluene (4 mL) was stirred at 120° C. for 75 hours. Ethyl acetate (10 mL) was then added, and the reaction was filtered through a pad of celite. The filtrate was then concentrated to dryness. The resulting residue was purified by chromatography (hexane:ethyl acetate, 1:1) to give tert-butyl 4-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.068 g, 56%) as a solid. MS APCI (+) m/z 554.4 detected.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:20])[CH:6]=[C:7]([S:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:8]2=[O:13]>C(Cl)(Cl)Cl.CC(O)=O.C([O-])(=O)C.[Ag+]>[C:16]([O:18][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:20])[CH:6]=[C:7]([S:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[C:8]2=[O:13])(=[O:17])[CH3:15]
Reactant: CC(SC1=CC(=O)c2c(CBr)cccc2C1=O)C(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1cccc2c1C(=O)C=C(SC(C)C(=O)O)C2=O
Reaction time: 8 h

Procedure:
A mixture of the brominated acid 1b (6 mmol) and silver acetate (2.2 g, 13.2 mmol) is combined in 20 mL of CHCl3 and 40 mL of AcOH, heated at 95° to 100° C. with vigorous stirring overnight. The solvent was evaporated in vacuo, and the residue was poured onto ice water saturated with NaCl. The crude product and AgCl were collected by filtration and washed with water. The solid was then added to a CHCl3, and the insoluble AgCl was removed by filtration. The AgCl was washed with CHCl3 until the washings were colorless. The combined CHCl3 solutions were dried with Na2SO4, concentrated and chromatographed on a silica gel column (C6H6 -CHCl3, 1:1, v/v). To yield (5-acetoxymethyl-1,4-naphthoquinonyl thio)-propionic acid, designated 1c.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH2:35]([S:39](Cl)(=[O:41])=[O:40])[CH2:36][CH2:37][CH3:38]>CN(C=O)C>[CH2:35]([S:39]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:17]=2[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]1)(=[O:41])=[O:40])[CH2:36][CH2:37][CH3:38]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1

Procedure:
Compound A29 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μl), butane-1-sulfonyl chloride (8 mg, 0.056 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 0.98 (t, 3H), 1.51 (m, 2H), 1.83 (m, 2H), 2.07 (m, 4H), 2.97 (m, 2H), 3.08 (s, 3H), 3.40 (m, 2H), 3.58 (m, 2H), 5.68 (m, 1H), 7.87 (d, 2H), 7.98 (d, 2H), 8.41 (s, 1H), 10.21 (s, 1H). Exact mass calculated for C20H27N5O7S2 513.14, found 514.4 (MH+).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:18](O)[CH2:19][Cl:20].O>C1(C)C=CC=CC=1.C(OC(C)C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:20][CH2:19][CH2:18][O:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCl
Reactant: O=C1c2ccccc2C(O)N1c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(OCCCl)N1c1ccccc1
Yield: 73 %

Procedure:
3-(2-Chloroethoxy)-2-phenyl-isoindolin-1-one can be obtained by refluxing a solution of 3-hydroxy-2-phenyl-isoindolin-1-one (22.5 g.) and glycol monochlorohydrin (7.7 g.) in anhydrous toluene (200 cc.) in the presence of p-toluenesulphonic acid (0.5 g.) in a Dean-Stark apparatus. Heating is continued until all the water formed has been entrained azeotropically. The cooled reaction mixture is then washed with 2N sodium hydroxide solution (50 cc.) and then with water (2 × 50 cc.). The organic solution obtained is dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue obtained is taken up in diisopropyl ether (50 cc.) and the insoluble product is filtered off and washed with diisopropyl ether (6 cc.). After drying, 3-(2-chloroethoxy)-2-phenyl-isoindolin-1-one (20.1 g.), which melts at 71°C., is obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH3:35]COCC.O>O1CCOCC1>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:11][CH3:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: OC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CI
Solvent: O
Product: COC(COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
NaNH2 (0.616 g, 15.0 mmol) was added to a flame-dried two-necked 50 ml round bottom flask equipped with a reflux condenser which contained a solution of rac-1-O-benzyl-3-O-tritylglycerol (5.30 g, 12.5 mmol) in anhydrous 1,4 dioxane (30 ml). The reaction mixture was refluxed for one hour under N2. Then CH3I (3.55 g, 25.0 mmol) was added dropwise. The resulting reaction mixture was refluxed overnight. After the mixture had cooled to room temperature, ether and H2O were added. The ether layer was removed and extracted with 1N HCl, H2O, sat. NaHCO3, H2O, and brine. The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give a yellow oil which solidified upon standing. The crude solid was recrystallized with hexanes to yield pure compound 13, rac-1-O-benzyl-2-O-methyl-3-O-tritylglycerol (4.32 g, 78.9%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[S:16][C:15]([CH3:17])=[N:14][C:13]=3[CH:18]=2)[CH:5]=[N:4][CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:17][C:15]1[S:16][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[CH:5]=[N:4][CH:3]=[C:2]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[N:7]=3)=[CH:18][C:13]=2[N:14]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1nc2cc(Nc3cncc(Cl)n3)ccc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nc2cc(Nc3cncc(-c4ccncc4)n3)ccc2s1
Yield: 86.7 %

Procedure:
A mixture of 2,6-dichloropyrazine (0.150 g, 1.006 mmol), 5-amino-2-methylbenzothiazole (0.250 g, 1.51 mmol), BINAP (0.0137 g, 0.02215 mmol), sodium tertiary butoxide (0.136 g, 1.409 mmol) and palladium acetate (0.005 g, 0.02215 mmol) in toluene (8 mL) was heated at 85° C. for 16 h under nitrogen. CH2Cl2 was added, the reaction mixture was filtered through Celite, and the solvent was evaporated. The residue was purified by column chromatography (5% methanol in CH2Cl2 as eluent) to give 0.180 g (65%) of intermediate (6-chloro-pyrazin-2-yl)-(2-methyl-benzothiazol-5-yl)-amine. 1H NMR (CDCl3) δ 7.59-7.54 (d, J=15.6 Hz, 2H), 7.38 (s, 1H), 7.19-7.16 (d, J=8.65 Hz, 1H), 6.98-6.95 (d, J=8.41 Hz, 1H), 6.71 (brs, 1H, NH), 2.31 (s, 3H, CH3); MS (API-ES/Positive); m/z: 277 (M+H)+. A mixture of (6-chloro-pyrazin-2-yl)-(2-methyl-benzothiazol-5-yl)-amine (0.075 g, 0.271 mmol), pyridine-4-boronic acid (0.040 g, 0.326 mmol), sodium carbonate (0.143 g, 1.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.0156 g, 0.0135 mmol) in DME:water (3:2, 5 mL) was heated at reflux for 20 h. The reaction mixture was concentrated under reduced pressure and the residue obtained was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to yield 2-methyl-N-(6-pyridin-4-ylpyrazin-2-yl)-1,3-benzothiazol-5-amine (0.075 g, 86.5%) as a yellow solid. 1H NMR (CD3OD) δ 8.82 (m, 3H), 8.72 (s, 1H), 8.45-8.44 (m, 2H), 8.35 (s, 1H), 7.92-7.90 (d, J=8.67 Hz, 1H), 7.61-7.59 (dd, J=10.63, 1.94 Hz, 1H), 2.89 (s, 3H, CH3); MS (API-ES/Positive); m/z: 320 (M+H)+.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27][S:28][C:29]#[N:30])[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[CH:17]=[N:18][N:19]([C@@H:21]3[CH2:22][CH2:23][C@H:24]([CH2:27][S:28][C:29]#[N:30])[CH2:25][CH2:26]3)[CH:20]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CSC#N)CC4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: N#CSC[C@H]1CC[C@@H](n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl thiocyanate was dissolved in methanol (2.0 mL, 0.049 mol) and DCM (2.0 mL, 0.031 mol), and TFA (0.5 mL, 0.006 mol) was added. The resulting mixture was stirred at 25° C. for 16 hours. TLC analysis showed no starting material present and LCMS analysis showed product. The reaction was concentrated using a rotary evaporator and the concentrate was chromatographed on silica gel using 2% MeOH/EtOAc to give the product. LC/MS (M+H)+: 339, 1H NMR (CD3OD) δ 8.65 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.50 (d, 1H), 6.96 (d, 1H), 4.43 (m, 1H), 3.20 (d, 2H, J=7.6 Hz), 2.24 (m, 2H), 1.80-2.17 (m, 7H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[NH:15][C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[C:18](O)=O)[CH2:4][CH2:3]1.[Cl-:24]>ClCCl>[ClH:24].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[NH:15][C:16](=[O:23])[C:17](=[CH:21][CH:22]=2)[CH2:18][Cl:24])[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccccc2-c2ccc(C(=O)O)c(=O)[nH]2)CC1
Reactant: [Cl-]
Solvent: ClCCl
Product: CN1CCN(c2ccccc2-c2ccc(CCl)c(=O)[nH]2)CC1
Product: Cl

Procedure:
A mixture of 3.44 g. of finely divided 6-[o-(4-methyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinic acid and 35 ml. of thionly chloride is stirred at room temperature for 16 hours, then diluted with 150 ml. of dichloromethane. The resulting solution is evaporated at reduced pressure and the resulting precipitate of 6-[o-(4-methyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride hydrochloride is collected by filtration, washed with dichloromethane and dried.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO.O>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1ccc(Cl)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1ccc(Cl)cc1Br
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A solution of 2-bromo-4-chlorobenzaldehyde (21.95 g; 100.0 mmol) in 200 mL methanol was stirred and cooled in an ice bath for 15 minutes, and solid sodium borohydride (1.9 g; 50.0 mmol) was added. A yellow color formed and there was copious gas evolution. Stirring was continued in the bath for 1 hour. The solution was diluted with 200 mL water, and then the methanol was evaporated on a rotary evaporator. The residual mixture was extracted with 200 mL EtOAc. The organic layer was washed with 50 mL brine, then dried over sodium sulfate and evaporated. The residual solid was washed out of the flask with hexane and collected by filtration, ground with a mortar and pestle to break up the chunks, then washed with hexane and air-dried on the filter to give 17.8 g of (2-bromo-4-chlorophenyl)methanol as a white solid.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=1)(=O)=O.[CH3:16]O>>[CH3:16][O:5][CH2:6][CH2:7][C:8]1[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=1
Reactant: CO
Reactant: CS(=O)(=O)OCCc1c[nH]c(=O)[nH]c1=O
Product: COCCc1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
6.0 g of 5-(2-methylsulphonyloxyethyl)-uracil are suspended in 100 ml of absolute methanol and the suspension is heated to 120°-130° C. for one hour in a pressure vessel. After cooling to room temperature, the crystals obtained are filtered off and washed with methanol. 5-(2-Methoxyethyl)-uracil, melting point 232°-234° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([Cl:11])[N:6]=1.[F:17][C:18]([F:24])([F:23])[CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:2][CH2:3][CH2:12][CH:13]([CH3:16])[CH3:14].[Cl:11][C:7]1[N:6]=[C:5]([N:4]([CH2:21][CH2:20][CH2:19][C:18]([F:24])([F:23])[F:17])[C:3]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:2]=2[F:1])[CH:10]=[CH:9][N:8]=1
Reactant: FC(F)(F)CCCBr
Reactant: Cc1ccc(F)c(Nc2ccnc(Cl)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC(C)C
Product: Cc1ccc(F)c(N(CCCC(F)(F)F)c2ccnc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
4-(2-Fluoro-5-methylanilino)-2chloropyrimidine (Reference Example A-10, 750 mg, 3.16 mmol), 4,4,4-trifluoro-1-bromobutane (725 mg, 3.80 mmol) and potassium carbonate (525 mg, 3.80 mmol) were dissolved in DMF (3 ml). The reaction mixture was stirred at room temperature for 12 hours and then evaporated onto silica (5 ml) and purified by column chromatography eluting with EtOAc (0–40%):isohexane to give the title product as a solid on evaporation (976 mg). NMR (300 MHz, 373K): 1.79 (m, 2H), 2.28 (m, 2H), 2.33 (s, 3H), 3.91 (t, 2H), 6.19 (d, 1H), 7.28 (m, 3H), 8.03 (d, 1H); m/z (EI+) 347 (M+).