Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH2:25][CH2:26][CH3:27]>O>[CH2:24]([N:11]1[CH2:12][CH2:13][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])([OH:14])[CH2:10]1)[CH2:25][CH2:26][CH3:27]
Reactant: OC1(c2cccc(F)c2F)CCNC1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCN1CCC(O)(c2cccc(F)c2F)C1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
In a sealed tube a mixture of enantiomer E2 of 3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.5 g, 2.5 mmol), acetonitrile (20 mL), potassium carbonate (0.69 g, 5 mmol) and n-butylbromide (0.25 mL, 2.6 mmol) was stirred at ambient temperature for 30 min after which an additional amount of n-butylbromide (0.12 mL, 1.25 mmol) was added and the mixture was stirred for 1 h. Water was added and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:1) gave the title compound (0.35 g). [α]D=−26° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 155.3° C.; MS m/z (relative intensity, 70 eV) 255 (M+, 8), 182 (30), 98 (25), 57 (16), 212 (bp).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][CH2:19][O:20][CH3:21])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][CH2:19][O:20][CH3:21])[CH:17]=2)=[N:31]\[OH:32])=[CH:4][CH:3]=1
Reactant: COCCn1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccc1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COCCn1cc(/C(CC(c2ccc(Br)cc2)c2ccccc2C)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-(2-methoxy-ethyl)-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless amorphous solid, MS (ESI+): m/z=469.2 [M+H]+.
Reaction SMILES: S([O-])(O)=O.[Na+].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:15]=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(OCC)(=O)C.[C-:30]#[N:31].[K+]>O>[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:15]([OH:16])[C:30]#[N:31])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(O)C#N
Reaction time: 8 h

Procedure:
A solution of sodium hydrogensulfite (0.92 g) in water (5 ml) is added to a suspension of (2S)-2-(tert-butoxycarbonyl)amino-3-phenylpropanal (2.00 g, Reference compound No. 2-1) in water (20 ml) under ice cooling, then the temperature is raised to room temperature, and the mixture is stirred overnight. Ethyl acetate (100 ml) is added to the mixture, and the whole is stirred for one hour. Then, a solution of potassium cyanide (0.58 g) in water (5 ml) is added thereto, and the whole is further stirred for four hours. The reaction mixture is extracted with ethyl acetate, and the extract is washed with saturated brine. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled reference compound (1.18 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2=[O:12].Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[N:14][OH:15])[C:5]2=[O:12]
Reactant: NO
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1C(=NO)Nc2ccc(Br)cc21
Yield: 76 %

Procedure:
3.3 g of 5-bromoisatin, 0.8 g of hydroxylamine hydrochloride and 1.6 g of sodium acetate are held at reflux in 50 ml of water for 1.5 hrs. The yellow crystals are filtered off and dried. 2.11 g of 5-bromoisatin oxime are isolated. Yield: 83%. M.p.=215° (decomposition).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[F:20].C[Al](C)C.[NH:25](/[C:29](/[CH3:35])=[CH:30]\[C:31](OC)=[O:32])[C:26]([CH3:28])=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:31](=[O:32])[CH:30]=[C:29]([CH3:35])[N:25]=[C:26]2[CH3:28])=[CH:15][C:14]=1[F:20]
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(NCCc2cc3ccccc3[nH]2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(NCCc3cc4ccccc4[nH]3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a solution of N1-(2-(1H-indol-2-yl)ethyl)-2-fluorobenzene-1,4-diamine (2.09 g, 7.76 mmol) in CH2Cl2 (30 mL) was added trimethylaluminium (19.4 mL, 38.8 mmol, 2 M in toluene) slowly. The mixture was stirred at rt for 1 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (2.44 g, 15.52 mmol) in CH2Cl2 (10 mL). The reaction mixture was stirred further at rt for 72 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a pale yellow solid (0.95 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)O1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[C:29]2[CH3:33])[N:24]=[N:25][CH:26]=1>>[ClH:20].[CH3:33][C:29]1[N:28]([CH2:27][C:23]2[N:24]=[N:25][CH:26]=[C:21]([C:9]3[CH:18]=[CH:17][C:16]4[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=4[CH:10]=3)[CH:22]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2ccc3c(c2)CCCC3)OC1(C)C
Product: Cc1nccn1Cc1cc(-c2ccc3c(c2)CCCC3)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=305.3 (M+H+), was prepared from 4,4,5,5-tetramethyl-2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:42][N:43](C)[OH:44].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([N:43]([O:44][CH3:29])[CH3:42])=[O:13])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc(COc2nc(C)n(-c3cc(C(=O)O)ccc3C)c(=O)c2Cl)c1
Reactant: CN(C)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)c3)c(Cl)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 3-[5-chloro-2-methyl-4-(3-methyl-benzyloxy)-6-oxo-6H-pyrimidin-1-yl]-4-methyl-benzoic acid from Step C (220 mg, 0.56 mmol) in tetrahydrofuran (2 mL) was added 1,1′-carbonyldiimidazole (136 mg, 0.84 mmol). After stirring at ambient temperature for one hour, N,N-dimethylhydroxylamine HCl (81 mg, 0.84 mmol) and triethylamine (0.15 mL, 1.12 mmol) were added. The solution continued to stir for eighteen hours. The solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, water, 5% citric acid and brine and dried over magnesium sulfate. The slurry was filtered and concentrated to provide the amide as a brown oil (193 mg, 78%). MS (M+H): 442
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=3)=[CH:20][NH:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CN(C)C=O.C(OCC)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][O:4][C:5]4[CH:13]=[CH:12][CH:11]=[C:10]5[C:6]=4[CH:7]=[CH:8][NH:9]5)[CH2:28][CH:29]=3)=[CH:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: ClCCOc1cccc2[nH]ccc12
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1ccc2c(C3=CCN(CCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-2-(1H-indole-4-oxy)ethane (0.359 g, 1.85 mmol) and 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.500 g, 2.13 mmol) in the presence of 2.0 equivalents of potassium carbonate (0.51 g, 3.7 mmol) in dimethylformamide at 90° C. Yield 0.101 g (14%) of a tan foam. The oxalate salt was prepared by treating the free base with 1.0 equivalent of oxalic acid in diethyl ether and evaporating. mp 120°-124° C. (browns) FDMS m/e=391 (M+ of free base).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH3:34][O:35][C:36]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][CH2:44]2)[CH:40]=[CH:39][C:37]=1[NH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][C:37]3[CH:39]=[CH:40][C:41]([N:43]4[CH2:44][CH2:45][N:46]([S:49]([CH3:52])(=[O:51])=[O:50])[CH2:47][CH2:48]4)=[CH:42][C:36]=3[O:35][CH3:34])[N:7]=2)[CH:18]=1
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: OCC(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 100 °C
Yield: 72.2 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(methyloxy)-4-[4-(methylsulfonyl)-1-piperazinyl]aniline (Example 232, step B) (51 mg, 0.18 mmol), and p-toluenesulfonicacid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (92 mg, 0.13 mmol, 73%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 9.40 (s, 1H), 8.49 (s, 1H), 8.33 (s, 1H), 8.21 (d, J=5.13 Hz, 1H), 8.05 (d, J=7.70 Hz, 1H), 7.82 (d, J=7.70 Hz, 1H), 7.73 (d, J=8.80 Hz, 1H), 7.61 (t, J=7.70 Hz, 1H), 7.43-7.49 (m, 2H), 7.35-7.43 (m, 1H), 7.16-7.24 (m, 2H), 6.99 (t, J=6.78 Hz, 1H), 6.73 (d, J=2.20 Hz, 1H), 6.52 (dd, J=8.62, 2.38 Hz, 1H), 6.48 (d, J=5.13 Hz, 1H), 3.81 (s, 3H), 3.25 (br. s., 8H), 2.92 (s, 3H); MS (ESI): 711 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:16])=[C:10]([CH2:12][C:13]([OH:15])=O)[CH:11]=1.Cl.[NH2:18][C:19]1([C:27]([O:29][CH3:30])=[O:28])[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]1.C(N(CC)CC)C>O1CCCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:16])=[C:10]([CH2:12][C:13]([NH:18][C:19]2([C:27]([O:29][CH3:30])=[O:28])[CH2:24][CH2:23][C:22]([F:26])([F:25])[CH2:21][CH2:20]2)=[O:15])[CH:11]=1
Reactant: COC(=O)C1(N)CCC(F)(F)CC1
Reactant: Cc1ccc(Br)cc1CC(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCC(F)(F)CC1
Temperature: 80 °C

Procedure:
36.5 ml (500 mmol) of thionyl chloride were added to 22.91 g (100 mmol) of (5-bromo-2-methylphenyl)acetic acid (EP 1791816 A1 and WO 2006/29799 A1), and the mixture was stirred at 80° C. until the evolution of gas was complete and then concentrated. The residue was dissolved in 100 ml of tetrahydrofuran (THF) (solution A). 25.3 g (110 mmol) of the compound from Example 4A were initially charged in 308 ml of THF, 21.3 ml of triethylamine were added dropwise at 20° C., solution A was then added dropwise with cooling and the mixture was stirred at room temperature until the reaction had gone to completion. The precipitate is filtered off with suction and washed with THF, the filtrate is concentrated under reduced pressure and the residue is recrystallized from methyl tert-butyl ether. This gave 33.6 g (83% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[O:10]C(C)(C)CN=2)[CH:6]=[CH:7][CH:8]=1.C([Li])C[CH2:18][CH3:19].C(I)C.[Cl-].[NH4+].[O:26]1CCCC1>Cl.O.CO>[CH2:18]([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[C:9]([OH:10])=[O:26])[CH3:19]
Reactant: [Li]CCCC
Reactant: COc1cccc(C2=NCC(C)(C)O2)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCI
Solvent: O
Product: CCc1c(OC)cccc1C(=O)O
Temperature: -65 °C

Procedure:
A 5 L, 4-necked round-bottom flask equipped with addition funnel, overhead stirring, and nitrogen purge was dried and charged with 128 g (623 mmoles) of 2-(3-methoxyphenyl)-5,5-dimethyloxazoline in 2.5 L of tetrahydrofuran. The mixture was cooled to -65° C. in a dry ice/isopropanol bath, and 450 mL of 1.6N n-butyl lithium was added slowly. After complete addition, the mixture was stirred for 1.5 hours at -45° to -30° C. After cooling to -45° C., ethyl iodide was added (80 mL, 1 mole). The temperature was maintained at -45° C. for 20 minutes, the mixture was allowed to warm to room temperature and was stirred overnight. Saturated ammonium chloride was added with ice cooling, and the mixture extracted several times with ether. The organic extracts were combined, dried over sodium sulfate, and solvent was removed in vacuo to give an oily solid. The solid was dissolved in 1 L of 6N hydrochloric acid in 3:1 water:methanol and heated at reflux for 15 hours. The hydrolysis was monitored by 1H NMR and shown to be about 75% complete. Additional acid was added (200 mL of 6N hydrochloric acid in 3:1 water:methanol), and the mixture was heated again at reflux for 8 hours. The mixture was cooled on ice, solids were collected, and dissolved in 10% aq. sodium hydroxide/methylene chloride. The aqueous layer was removed, acidified, and filtered to yield a tan solid which was air-dried at room temperature (53 g). An additional 23 g of product was obtained by further acidic hydrolysis of the methylene chloride extract. The melting point of the desired acid was 100°-101° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[N:6][CH:7]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28])#[N:21].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:28][C:27]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[N:4][C:5]([NH:8][CH2:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)([CH3:12])[CH3:11])=[N:6][CH:7]=2)=[CH:23][C:22]=1[C:20]#[N:21]
Reactant: CC(C)(CNc1ncc(Br)cn1)c1ccc(F)cc1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(CNc1ncc(-c2ccc(F)c(C#N)c2)cn1)c1ccc(F)cc1
Temperature: 120 °C
Yield: 75.5 %

Procedure:
To a 5 mL microwave reaction vessel was added 5-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyrimidin-2-amine (267 mg, 0.8 mmol, 1.0 equiv), 3-cyano-4-fluorophenylboronic acid (203 mg, 1.2 mmol, 1.5 equiv), Cl2Pd(dppf) (60 mg, 82 μmol, 0.1 equiv), potassium carbonate (1.2 mL of a 2N aqueous solution, 2.4 mmol, 3.0 equiv), and dioxane (4 mL). The reaction was heated in a microwave reactor at 120° C. for 20 min. The aqueous layer was removed from the reaction, and the organic layer was directly purified by reverse phase column chromatography to give 220 mg (73%) of 2-fluoro-5-(2-(2-(4-fluorophenyl)-2-methylpropylamino)pyrimidin-5-yl)benzonitrile as a white solid.
Reaction SMILES: [C:1](=[O:16])([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[O:2][CH2:3]Cl.[I-:17].[Na+]>CC(C)=O>[C:1](=[O:16])([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[O:2][CH2:3][I:17]
Reactant: COCCOCCOCCOC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COCCOCCOCCOC(=O)OCI
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
Chloromethyl 2-(2-(2-methoxyethoxy)-ethoxy)-ethyl carbonate (9 g) was added to a solution of sodium iodide (21.07 g) in acetone (45 ml). After stirring at 40° C. for 2.5 hours the reaction mixture was cooled in ice, filtered and evaporated in vacuo. The residue was taken up in dichloromethane, washed with aqueous sodium bicarbonate and sodium thiosulfate, dried over magnesium sulfate, filtered and evaporated in vacuo. Purification on silica gel with petroleum ether/ethyl acetate (1:1) as eluent gave the title compound as a light yellow oil.
Reaction SMILES: OO.[CH2:3]([C:5]1[N:6]=[N+:7]([O-:20])[C:8]2[C:17]3[CH2:16][N:15]([CH3:18])[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[N:19]=1)[CH3:4].C(O)(C(F)(F)F)=[O:22]>C(Cl)Cl.N>[CH2:3]([C:5]1[N:6]=[N+:7]([O-:20])[C:8]2[C:17]3[CH2:16][N:15]([CH3:18])[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[N+:19]=1[O-:22])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCc1nc2ccc3c(c2[n+]([O-])n1)CN(C)CC3
Agent: N
Agent: OO
Solvent: ClCCl
Product: CCc1n[n+]([O-])c2c3c(ccc2[n+]1[O-])CCN(C)C3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 18.4 %

Procedure:
H2O2 (70%, 0.5 mL, ca. 5 mmol) was added dropwise to a stirred solution of TFM (0.7 mL, 5 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 264 (120 mg, 0.5 mmol) and TFA (0.19 mL, 2.5 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (20 mL) and extracted with DCM (4×100 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-8%) of MeOH/DCM, to give 1,4-dioxide 265 (24 mg, 19%) as a red solid: mp 117-121° C.; 1H NMR δ 8.35 (d, J=8.8 Hz, 1H, H-5), 7.70 (d, J=8.8 Hz, 1H, H-6), 4.41 (s, 2H, H-10), 3.18 (q, J=7.5 Hz, 2H, CH2), 3.12 (br t, J=5.8 Hz, 2H, H-7), 2.74 (t, J=5.8 Hz, 2H, H-8), 2.58 (s, 3H, NCH3), 1.42 (t, J=7.5 Hz, 3H, CH3); MS (APCI) m/z 261 (MH+, 100%); HRMS (FAB+) calcd for C13H17N4O2 (MH+) m/z 261.1352, found: 261.1354.
Reaction SMILES: [CH2:1]([NH:12][C:13]1[N:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][N:14]=1)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.S(OC)(O[CH3:27])(=O)=O>C1COCC1>[OH-:5].[CH3:27][N+:18]1[CH:17]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=[N:14][C:13]=1[NH:12][CH2:1][C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: COC(=O)c1cnc(NCc2ccc(OC)c(OC)c2)nc1
Reactant: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COC(=O)c1cnc(NCc2ccc(OC)c(OC)c2)[n+](C)c1
Product: [OH-]
Yield: 76 %

Procedure:
A mixture of 2.62 g .(8.6 mmol) of 2-veratrylamino-5-methoxycarbonylpyrimidine and 3.28 ml (4 eq) of dimethyl sulfate in 60 ml of anhydrous THF is refluxed for forty-eight hours. The mixture is extracted with ethyl acetate and water. Purification on silica gel (eluent: 3% MeOH/CH2Cl2 /NH3 in aqueous solution at 33%, 5.5 ml/100) of the oil resulting from evaporation of the aqueous phases gives 2.2 g of salt (yield: 76%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.[C:11]1([CH3:29])[CH:16]=[CH:15][C:14]([S:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:19])=[O:18])=[CH:13][CH:12]=1>CO>[C:11]1([CH3:29])[CH:12]=[CH:13][C:14]([S:17]([OH:20])(=[O:18])=[O:19])=[CH:15][CH:16]=1.[CH2:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C1=NCCc2ccccc21
Reactant: CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CO
Product: CCCCCCCCN1CCc2ccccc2C1
Product: Cc1ccc(S(=O)(=O)O)cc1
Yield: 7.4 %

Procedure:
3,4-Dihydroisoquinoline (1.31 g, 10.0 mmol) was dissolved in 3 ml MeOH in a 3-neck 25 ml round bottom flask fitted with a condenser, drying tube and stirrer bar, and cooled in an ice bath. n-Octyl p-toluenesulfonate (2.84g, 10.0 mmol)*, dissolved in 7.0 ml methanol, was added dropwise over about 7 minutes via an addition funnel. The ice bath was removed and replaced with an oil bath and the colorless clear solution heated to reflux for at least 8 hours during which time the reaction solution turned yellow. Removal of the methanol in vacuo gave slightly colored solid product which was triturated with about 7.5 ml acetone. The acetone insoluble solids were filtered, washed with more acetone and dried in a vacuum desiccator. Yield of colorless solids was 1.91 g. A second batch of solids was recovered from the acetone filtrate/washing and filtered, washed with acetone and dried to give 0.31 gm colorless solids.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:28])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:29]=[CH:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH:29](/[C:2]1[N:3]=[C:4]([NH2:28])[C:5]2[N:6]=[C:7]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])=[CH:30]\[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Nc1nc(I)nc2c1nc(NCc1ccccc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C=CCCCC
Product: CCCC/C=C/c1nc(N)c2nc(NCc3ccccc3)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reaction time: 0.58 h

Procedure:
The reaction was performed with 2-iodo-8-benzylaminoadenosine (11, 410 mg, 0.82 mmol) and (E)-1-borocatechol)-1-hexene (2.47 mmol). The mixture was purified by column chromatography (10% MeOH in CH2Cl2). Yield 41 mg (0.10 mmol, 11%), mp 153–155÷C; 1H NMR (MeOD-d4) δ 7.64 (t, 1H, J=6.10 Hz, NH), 7.36–7.18 (m, 5H, phenyl), 6.59 (bs, 2H, NH2), 6.94–6.80 (m, 1H, ═CHCH2), 6.28 (d, 1H, J=15.42 Hz, ═CH), 5.92 (d, 1H, J=7.71 Hz, H-1′), 5.77 (t, 1H, J=4.85 Hz, OH-2′), 5.32 (d, 1H, J=6.74 Hz, OH-5′), 5.18 (d, 1H, J=4.18 Hz, OH-3′), 4.64 (q, 1H, J=4.64 Hz, H-2′), 4.58 (t, 2H, J=4.65 Hz, NHCH2), 4.09 (t, 1H, J=4.09 Hz, H-3′), 3.98 (d, 1H, J=1.60 Hz, H-4′), 3.62 (q, 2H, J=2.58 Hz, H-5′), 2.29–2.05 (m, 2H, ═CHCH2), 1.72–1.20 (m, 4H, CH2CH2), 1.00–0.83 (m, 3H, CH3) ppm; MS m/z 456 (M+H)+; HPLC, System A: 20–100% CH3CN in H2O in 35 min., retention time=9.61 min.; System B: 30–100% CH3OH in H2O in 40 min., retention time=26.10 min.