Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11](O)=[O:12])C)=O)(C)(C)C.[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:26][O:27][CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1>>[CH3:6][NH:8][CH2:10][C:11]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:26][O:27][CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1)=[O:12]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Product: CCOC(=O)C(=NOC)c1csc(NC(=O)CNC)n1

Procedure:
The subtitle compound was prepared from N-[tert-butoxycarbonyl]sarcosine (2.00 g) and ethyl 2-amino-alpha-[methoxyimino]-4-thiazoleacetate (2.66 g) by the method of example 10 step (i).Yield 2.77 g.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH:35]1(O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O.O1CCOCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[N:32]=[CH:31][C:30]([O:33][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:29][N:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ncc(O)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OC1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CCCCc1nc(C)n(-c2ncc(OC3CCCCC3)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56.2 %

Procedure:
Process 1: 4′-{[4-butyl-1-(5-hydroxypyrimidin-2-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (27 mg, 0.060 mmol), cyclohexanol (12 mg, 0.120 mmol) and triphenylphosphine (32 mg, 0.122 mmol) were dried for 3 hrs in vacuo, purged with argon, added 1,4-dioxane (1 mL) and diethyl azodicarboxylic acid (2.2 mol/L toluene solution, 70 μL, 0.154 mmol), and then stirred at 80° C. for 3 hrs. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (chloroform:methanol=10:1) to obtain 4′-{{4-butyl-1-[5-(cyclohexyloxy)pyrimidin-2-yl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl}biphenyl-2-carbonitrile (18 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4](Cl)[N:3]=1.[C:20]1([CH2:26][O:27][C:28]2[CH:36]=[CH:35][C:31]3[NH:32][CH:33]=[N:34][C:30]=3[CH:29]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC1C=CC=CC=1)C1C=CC=CC=1.N1C2C=CC=CC=2NC=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([N:34]2[C:30]3[CH:29]=[C:28]([O:27][CH2:26][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:36]=[CH:35][C:31]=3[N:32]=[CH:33]2)[N:3]=1
Reactant: c1ccc(COc2ccc3[nH]cnc3c2)cc1
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)nc(Cl)nc21
Agent: c1ccc2[nH]cnc2c1
Solvent: CCCCO
Solvent: c1ccc(COCc2ccccc2)cc1
Product: C[Si](C)(C)CCOCn1cnc2c(-n3cnc4ccc(OCc5ccccc5)cc43)nc(Cl)nc21
Temperature: 120 °C
Yield: 48.8 %

Procedure:
860 mg of product obtained in stage 1 above are mixed with 605 mg of 5-(phenylmethoxy)-1H-benzimidazole (benzyl ether in the 5-position of benzimidazole) and 15 ml of butanol. The mixture is heated at 120° C. for 24 hours. Partial drying, washing with H2O and then drying under vacuum at 50° C. are carried out. 667 mg of 2-chloro-6-[6-(phenylmethoxy)-1H-benzimidazol-1-yl]-9-[[2-(trimethylsilyl)ethoxy]methyl]-9H-purine are obtained, in the form of beige-colored crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](=[O:13])[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Li+].[Br-].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8](=[O:13])[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(=O)ccc1C
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(C)ccc(=O)n1Cc1ccccc1
Temperature: 80 °C
Yield: 45.9 %

Procedure:
A flask was charged with 3-methyl-6-oxo-1,6-dihydro-pyridine-2-carboxylic acid ethyl ester (230 mg, 1.27 mmol), toluene (6.4 mL) and water (0.064 mL). K2CO3 (351 mg, 2.54 mmol), LiBr (221 mg, 2.54 mmol), tetrabutylammonium bromide (41 mg, 0.127 mmol), and benzyl bromide (0.23 mL, 1.91 mmol) were added, and the resulting suspension was heated at 80° C. for 40 min. The mixture was allowed to come to r.t., diluted with CH2Cl2, and filtered. The filtrate was concentrated in vacuo, and the residue was chromatographed (0-10% MeOH/CH2Cl2) to give 158 mg of the title compound as a viscous oil. MS: (+) m/z 272.31 (M+1).
Reaction SMILES: [Cl-].[CH3:2][S+:3]([CH3:6])([CH3:5])=[O:4].[H-].[Na+].C[SH+](C)=O.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](F)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[F:24][P-:25]([F:30])([F:29])([F:28])([F:27])[F:26].[H+]>O1CCCC1>[F:24][P-:25]([F:30])([F:29])([F:28])([F:27])[F:26].[CH3:2][S+:3]([CH3:6])([CH2:5][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)F)cc1
Reactant: C[S+](C)(C)=O
Agent: C[SH+](C)=O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)C[S+](C)(C)=O)cc1

Procedure:
Dimethylsulphoxonium methylide was prepared by the method described by Corey and Chaykovsky, loc. cit., from trimethylsulphoxonium chloride (25.7 parts) by treatment with sodium hydride (6.7 parts) in dry tetrahydrofuran. This ylide was converted into dimethylsulphoxonium p-toluenesulphonylmethylide by reaction with p-toluenesulphonyl fluoride (17.4 parts) using the method described by Truce and Madding, loc. cit. The toluenesulphonylmethylide was neutralised by the addition of 65% aqueous hexafluorophosphoric acid (49.5 parts) over 15 minutes, followed by concentration of the solution. The white solid which precipitated was filtered off, washed with water, and dried under vacuum to give 20 parts of the desired product (VI, R=p--CH3C6H4, R6 =H, R7 =R8 =CH3, q=t=1, Zt- =PF6-), mpt. 174°-5° C.; NMR (acetone -d6) 2.50 (s-3H), 4.23 (s-6H), 6.20 (s-2H), 7.5-8.2 (m-4H); IR (KBr disc) 3020, 3000, 2930, 2920, 1590, 1400, 1330, 1300, 1250, 1160, 1030, 940, 840, 750 cm-1 ; UV (ethanol) λmax 255 nm (data for product recrystallised from methanol).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:21]=[CH:20][C:6]([NH:7][C:8](=[O:19])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]([CH3:39])([CH3:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(O)C>[N:14]1([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([NH:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH2:29][CH2:30][CH2:31][C:32]([CH3:38])([CH3:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:21][CH:20]=2)=[O:19])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: O=C(CCCCCn1ccnc1)Nc1ccc(O)cc1
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCOc1ccc(NC(=O)CCCCCn2ccnc2)cc1
Reaction time: 8 h

Procedure:
In 50 ml of ethanol was suspended 3 g of 4'-hydroxy-6-(1-imidazolyl)hexaneanilide hydrochloride. While stirring 2.8 g of anhydrous potassium carbonate and 2.4 g of ethyl 5-bromo-2,2-dimethylpentanoate were added to the suspension. The mixture was stirred for 8 hours under reflux. The solvent was removed from the reaction mixture by distillation under reduced pressure and the residue was dissolved in ethylene chloride. The solution was successively washed with a 5% aqueous hydrogen sodium carbonate solution, water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation under reduced pressure. The resulting crystals were recrystallized from ethyl acetate to give the aimed product, ethyl 5-[p-[6-(1-imidazolyl)hexanamido]phenoxy]-2,2-dimethylpentanoate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl.C(=O)(O)[O-].[Na+]>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(/C=C/c2cccnc2)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Nc1cccc(/C=C/c2cccnc2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 39.6 %

Procedure:
A mixture of 3-[(E)-2-(3-nitrophenyl)vinyl]pyridine (3.64 g), iron powder (3.6 g) and hydrochloric acid (35%, 11 ml) in ethanol (30 ml) was stirred at 80° C. for 4 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-[(E)-2-(3-aminophenyl)vinyl]pyridine (1.25 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:17]([CH:18]=2)[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[S:14]3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:17]([C:18]=2[Br:23])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[S:14]3)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(-c2cn3c(n2)sc2ccccc23)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cccc(-c2nc3sc4ccccc4n3c2Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 30 ml of chloroform were added 1.35 g of 2-(m-acetoxyphenyl)imidazo[2,1-b]benzothiazole and 0.94 g of N-bromosuccinimide and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was washed with ether and dried to provide 2-(m-acetoxyphenyl)-3-bromoimidazo[2,1-b]benzothiazole. The product was suspended in 50 ml of methanol and after adding thereto 4 ml of 0.84 normal methanol solution of potassium hydroxide, the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added acetic acid to acidify the mixture and then 50 ml of water was added to the mixture to form crystals, which were recovered by filtration and recrystallized from a mixture of methylcellosolve and water to provide 1.2 g of 3-bromo-2-(m-hydroxyphenyl)imidazo[2,1-b]benzothiazole.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=1)[NH:6][C:7]2=[O:12].C(N(CC)CC)C.[CH2:32]([OH:36])[CH2:33][C:34]#[CH:35]>CN(C=O)C.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.[Cu]I>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[NH:6][C:7](=[O:12])[C:8]3[C:3]([CH:4]=2)=[C:2]([C:35]#[C:34][CH2:33][CH2:32][OH:36])[CH:11]=[CH:10][CH:9]=3)=[CH:14][CH:15]=1
Reactant: CN(C)CCOc1ccc(-c2cc3c(Br)cccc3c(=O)[nH]2)cc1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(-c2cc3c(C#CCCO)cccc3c(=O)[nH]2)cc1
Yield: 38.8 %

Procedure:
5-Bromo-3-[4-(2-dimethylaminoethoxy)phenyl]-2H-isoquinolin-1-one (50.0 mg, 0.130 mmol), triethylamine (1.1 mL, 8.36 mmol), dichlorobis(triphenylphosphine)palladium(II) (5.0 mg, 0.0065 mmol), copper (I) iodide (3.0 mg, 0.009 mmol), 3-butyn-1-ol (20 μL, 0.260 mmol) in DMF (1.1 mL) were added to a microwave vial and the reaction mixture purged with N2 for 5 min. The reaction mixture was irradiated using a microwave reactor (300 W, 100° C., 90 min). The reaction mixture was filtered through Celite® 545, diluted with DMSO and was purified by reverse phase preparative HPLC-MS to obtain 3-[4-(2-dimethylaminoethoxy)phenyl]-5-(4-hydroxybut-1-ynyl)-2H-isoquinolin-1-one as a brown solid (19.0 mg, 39%).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[N:6][N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19]C(=O)OCC3C=CC=CC=3)[CH2:11][CH2:10][NH:9][C:8]=12)(=[O:3])[NH2:2]>C(Cl)Cl.CO.[Pd]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:7]2[N:6]=[C:5]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]4[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=4)=[CH:32][CH:31]=3)[C:4]([C:1]([NH2:2])=[O:3])=[C:8]2[NH:9][CH2:10][CH2:11]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
To a solution of benzyl 2-(3-carbamoyl-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenylcarbamate (100 mg, 0.17 mmol) in 5 mL of DCM and 5 mL of CH3OH was added 10% w/w Pd/C (50 mg). After stirring at RT under H2 for 16 hr, the mixture was filtered and the cake was washed with DCM/CH3OH (1/1, 50 mL). The filtrate was concentrated and purified by chromatography column on silica gel eluting with DCM/CH3OH to afford 10 mg (13%) of 7-(2-aminophenyl)-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. 1H NMR (400 MHz, CD3OD-d4) δ 7.39 (d, J=8.8 Hz, 2H), 7.02-6.91 (m, 7H), 6.66 (d, J=7.6 Hz, 1H), 6.53 (t, J=7.6 Hz, 1H), 6.33 (d, J=7.6 Hz, 1H), 5.54-5.50 (m, 1H), 3.30-3.24 (m, 1H), 3.12-3.06 (m, 1H) and 2.31-2.20 (m, 2H). MS (ESI) m/e [M+1]+ 443.9.
Reaction SMILES: [H-].[Na+].[N:3]1([C:9](OC(C)(C)C)=O)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.BrC[C:18]1[CH:22]=[N:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:19]=1>CN(C)C=O>[C:23]1([N:20]2[N:21]=[C:22]([CH2:9][N:3]3[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]3)[CH:18]=[N:19]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCc1cnn(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-n2ncc(CN3CCNCC3)n2)cc1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 0.28 g (0.71 mmol) of sodium hydride (60% mineral oil dispersion) in 5 mL anhydrous N,N-dimethylformamide at 0° C. was added 0.12 g (0.65 mmol) tert-butyl 1-piperazine-carboxylate. The resulting mixture was stirred under an atmosphere of nitrogen for 15 min and then allowed to warm to ambient temperature at which point 0.14 g (0.59 mmol) of 4-(bromomethyl)-2-phenyl-2H-1,2,3-triazole was added. After 4 h, quench the reaction with 25 mL cold water and extract the resulting solution with 25 mL ethyl acetate. The organic layer was washed with water (2×25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to afford the title compound which was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). LC/MS: m/z (ES) 344.0 (MH)+.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].C1COCC1.[F:10][C:11]([F:19])([F:18])[C:12]([C:14]([F:17])([F:16])[F:15])=[O:13]>>[F:10][C:11]([F:19])([F:18])[C:12]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH:1]=[CH2:2]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C=C[Mg]Cl
Solvent: C1CCOC1
Product: C=CC(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
To 1.6 M vinylmagnesium chloride in THF (200 mL, 0.32 mol) at −78° C. was added hexafluoroacetone (50 g, 0.31 mol) by cannula over a period of 3 h with stirring. The reaction mixture was allowed to warm to r.t. and stirred for an additional 2 h, then heated to 40° C. for an additional 1 h. The reaction mixture was quenched with aqueous NH4Cl solution. The mixture was diluted with pentane, filtered, and the organic phase was dried over MgSO4. Fractional distillation (12 inch Vigreux column) at 100-103° C. afforded the product 1,1,1-trifluoro-2-trifluoromethyl-but-3-en-2-ol (mixture containing around 66 mol % THF) as a clear liquid (50 g). 1H NMR δ 5.20 (br, 1H), 5.70 (d, 1H), 5.92 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:44]=2)[C:42]#[N:43])O1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:37]3[CH:38]=[N:39][CH:40]=[C:41]([C:42]#[N:43])[CH:44]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@H](CO)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (S)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-(hydroxymethyl)pyrrolidin-1-yl)nicotinamide (Stage 174.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.05 min, m/z=498.5 [M+H]+, m/z=500.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.66 (m, 1H) 1.78-1.92 (m, 1H) 2.17-2.30 (m, 1H) 2.96 (dd, J=11.00, 6.85 Hz, 1H) 3.11-3.28 (m, 4H) 3.32-3.42 (m, 1H) 4.60 (t, J=5.26 Hz, 1H) 7.34 (d, J=9.05 Hz, 2H) 7.81-7.91 (m, 2H) 8.08 (d, J=2.20 Hz, 1H) 8.40 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.45 Hz, 1H) 8.91 (d, J=2.20 Hz, 1H) 9.01 (d, J=1.96 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH:15]([CH2:27][OH:28])[CH2:16][O:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20].[NH3:29]>>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH:15]([CH2:27][OH:28])[CH2:16][O:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])=[C:2]([NH2:29])[N:10]=1
Reactant: N
Reactant: CCOP(=O)(COCC(CO)On1cnc2c(Cl)nc(NC=O)nc21)OCC
Product: CCOP(=O)(COCC(CO)On1cnc2c(N)nc(N)nc21)OCC
Reaction time: 5 h
Yield: 28 %

Procedure:
A solution of 6-chloro-9-[1-(diethoxyphosphorylmethoxy)-3-hydroxyprop-2-oxy]-2-formamidopurine (400 mg, 0.91 mmol) in saturated ethanolic ammonia (20 ml) was placed in an autoclave and kept at 110° C. for 5 h. After cooling, the solvent was evaporated in vacuo and the residue chromatographed on silica, eluting with chloroform-methanol 10:1, affording 2,6-diamino-9-[1-(diethoxyphosphorylmethoxy)-3-hydroxyprop-2-oxy]purine (100 mg, 28%) as an oil. νmax (CHCl3) 3500, 3400, 1620 and 1600 cm-1 ; δH [(CD3)2SO] 1.24, (6H, t, J7.1 Hz, 2×CH2CH3), 3.58 (2H, m, CH2OH), 3.80 (2H, d, J5.0 Hz, CH2OCH2P), 3.92 (2H, d, J8.2 Hz, CH2P), 4.05 (4H,m,2×CH 2 CH3), 4.39 (1H, t, J5.0 Hz, CHON), 5.35 (1H, br.s, D2O exchangeable, OH), 6.00 (2H br.s, D2O exchangeable, NH2), 6.87 (2H, br.s, D2O exchangeable, NH2), 7.87 (1H, s, H-8); m/z (FAB+ve Ion), 391 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([NH:23][CH3:24])[CH:18]=1.Cl>O1CCOCC1>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]3[CH:18]=[C:19]([NH:23][CH3:24])[N:20]=[CH:21][N:22]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CNc1cc(Cl)ncn1
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)cc2)CC1
Temperature: 150 °C

Procedure:
A mixture of 4-(4-ethylpiperazin-1-yl)-aniline (1 g, 4.88 mmol) (prepared in analogy to Example 238, Step 238.1), (6-chloro-pyrimidin-4-yl)-methyl-amine (1.81 g, 12.68 mmol, 1.3 eq.) and 4N HCl in dioxane (15 ml) is heated in a sealed tube to 150° C. for 5 h. The reaction mixture is concentrated, diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 93:7) followed by trituration in diethyl ether affords the title compound as a white solid: ESI-MS: 313.2 [MH]+; tR=1.10 min (system 1); TLC: Rf=0.21 (DCM/MeOH, 93:7).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[C:5]2[OH:27].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:5]2[OH:27]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(Cl)c(Cl)cc21
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To 1,1-dimethylethyl N-((6,7-dichloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (235 mg, 567 μmol) was added TFA (2 mL) at ambient temperature. The mixture was stirred for 30 minutes and then concentrated, precipitated with ether, filtered, washed with ether, and dried in a vacuum oven to give the title compound (95 mg) as a white solid. MS (m/z)=358 (M+H)+. Calculated for C15H13Cl2NO5 357.02.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=O)[NH:5][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:7]=1[CH3:8]>C1COCC1>[CH3:1][C:2]1[CH2:3][CH2:4][NH:5][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[C:7]=1[CH3:8]
Reactant: CC1=C(C)C(c2ccccc2C)NC(=O)C1
Solvent: C1CCOC1
Product: CC1=C(C)C(c2ccccc2C)NCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4,5-dimethyl-6-o-tolyl-3,6-dihydro-1H-pyridin-2-one (177 mg; 0.82 mmol) in THF(5 mL) is treated with alane (10 equivalents) and the mixture is stirred at room temperature for 16 hours. The reaction is quenched with Na2SO4.10H2O (2 g) and the resulting mixture filtered and the insolubles washed with ethyl acetate. The filtrate is concentrated in vacuo to give the product (12).
Reaction SMILES: [C:1]([O:20][CH3:21])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C/C=C\CCCCCCCC.[C:22]([OH:28])(=[O:27])[C:23](C)([CH3:25])[CH3:24]>>[CH2:1]([O:20][CH2:21][C:23]([CH3:25])([CH3:24])[C:22]([OH:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Product: CC(C)(COCc1ccccc1)C(=O)O

Procedure:
The spectroscopic data of the compound have already been reported further back in the text. Nafion SAC 13 was used as catalyst for acyloxylating methyl oleate. The following reaction conditions were selected: catalyst velocity 4 mmol/g of catalyst, molar excess of pivalic acid compared to methyl oleate=25, temperature 120° C., batch reaction under atmospheric pressure, reaction time 24 h.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[I:12]I>C(O)C.[N+]([O-])([O-])=O.[Ag+]>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[I:12]
Reactant: II
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Product: Nc1c(I)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
Commercially available 4-chloro-2-nitro-phenylamine (17.4 g, 131.5 mmol) was dissolved in ethanol (300 mL), and thereto silver nitrate (27 g, 157.7 mmol) and iodine (40 g, 157.7 mmol) were added. The mixture was stirred for 8 hours at room temperature. At the end of reaction, the mixture was filtered using celite and washed with 100 ml of ethylacetate and concentrated. To the concentrate, added water and extracted with ethylacetate. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate to give 2-amino-5-chloro-3-nitro-phenyliodide (27.4 g, Yield 69%).