Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([OH:13])[CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[OH:14][CH2:15][CH2:16]C#N>>[C:15]([O:13][CH:11]([CH3:12])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[C:9]#[N:10])(=[O:14])[CH3:16]
Reactant: N#CCCO
Reactant: Cc1ccc(C(C#N)C(C)O)cc1
Product: CC(=O)OC(C)C(C#N)c1ccc(C)cc1

Procedure:
This ester was prepared using the procedure described in Example 5, except 2-(4-methylphenyl)-3-hydroxybutanenitrile in place of 2-2-chloro-5-(difluoromethoxy)phenyl)-3-hydroxypropanenitrile in the above described procedure. The preparation of 2-(4-methylphenyl)-3-hydroxybutanenitrile is described in Example 17. The recovered ester product was a colorless oil (85% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:30]=1)([O-])=O.C(OCC)(=O)C>CO.[Pd]>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:30][C:8]=4[N:9]=3)=[CH:13][CH:14]=2)[CH:19]=[C:20]([O:28][CH3:29])[C:21]=1[O:26][CH3:27]
Reactant: COc1cc(-c2ccc(-c3nc4cc([N+](=O)[O-])ccc4o3)cc2)cc(OC)c1OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc(-c3nc4cc(N)ccc4o3)cc2)cc(OC)c1OC
Reaction time: 4 h
Yield: 74.6 %

Procedure:
22 mg (0.0541 mmol) of 5-nitro-2-(3′,4′,5′-trimethoxy-[1,1′-biphenyl]-4-yl)benzo[d]oxazol e was dissolved in methanol, and then, 10% Pd/C was added thereto under hydrogen gas atmosphere. The mixed solution was stirred for 4 hours, and ethyl acetate was added thereto to filter with a celite pad. The filtered solution was concentrated under reduced pressure. Afterwards, the reaction solution was subjected to a silica gel column chromatography (ethyl acetate/normal-hexane at a volume ratio of 1:1) to obtain 15.2 mg (yield=74.6%) of 2-(3′,4′,5′-trimethoxy-[1,1′-biphenyl]-4-yl)benzo[d]oxazole-5-amine (Derivative #7).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.[CH3:23][O:24][CH2:25][CH:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C(I)C>>[CH3:23][O:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH:29]([N:1]2[CH2:2][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:20])([F:19])[F:21])[CH:16]=4)[NH:11][N:10]=3)[CH2:4]2)[CH2:28][CH2:27]1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: COCC1CCC(=O)CC1
Solvent: CCI
Product: COCC1CCC(N2CC(NC(=O)CNc3n[nH]c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 4-methoxymethyl-cyclohexanone (following the procedure described in Example 34, substituting methyl iodide for ethyl iodide) using the procedure described in Step E of Example 1.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>>[F:29][C:28]([F:31])([F:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:18]1[C:16]2[CH2:17][CH:13]([CH2:12][N:32]=[N+:33]=[N-:34])[O:14][C:15]=2[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(cccc3-c3ccccc3C(F)(F)F)O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2c(cccc2-c2ccccc2C(F)(F)F)O1
Yield: 94.1 %

Procedure:
Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2-(trifluoromethyl)phenylboronic acid (3.72 g, 17.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 4.5 g (77%) of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate as a yellow oil. Treatment of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (4.3 g, 9.59 mmol) with sodium azide (2.5 g, 38.46 mmol) generally according to the procedure described for Intermediate 98 gave 2.88 g (94%) of (±)-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl azide. Treatment of the azide with palladium on carbon (0.28 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.46 g (83%) of (±)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 213-215° C.; Anal. calcd. for C16H14F3NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.13; H, 4.65; N, 4.13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:23]=[CH:24]/[CH:25]=[CH:26]/[CH2:27][OH:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]>[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:23]=[CH:24]/[CH:25]=[CH:26]/[CH:27]=[O:28])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: COc1cc(/C=C/C=C/CO)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Product: COc1cc(/C=C/C=C/C=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Reference Example 35, (E,E)-5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadien-1-ol was subjected to oxidation with activated manganese dioxide to yield (E,E)-5-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadien-1-al, which was recrystallized from ethyl acetate to give colorless needles, m.p.133-134° C.
Reaction SMILES: [N:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9])=[O:2].[C:10]1([C:16]2[C:18](=[O:19])[C:17]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[C:4]1([CH3:9])[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]1[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18](=[O:19])[O:2]1
Reactant: O=c1c(-c2ccccc2)c1-c1ccccc1
Reactant: Cc1ccccc1N=O
Solvent: C1CCOC1
Product: Cc1ccccc1N1OC(=O)C(c2ccccc2)C1c1ccccc1

Procedure:
2.4 Parts of o-nitrosotoluene and 4.1 parts of diphenylcyclopropenone in 50 parts of tetrahydrofuran is heated at the reflux temperature for 48 hours. Solvent then is removed under reduced pressure and the residue is crystallized from cyclohexane. Recrystallization from ethanol gives, as red granules, 2-(o-tolyl)-3,4-diphenylisoxazolin-5-one, melting at about 142°-143° C. That compound is represented structurally by the following formula. ##STR6##
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([CH3:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc(Cl)ccc2CC1C
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1N=C(c2ccc(N)c(C)c2)c2cc(Cl)ccc2CC1C
Reaction time: 0.75 h
Yield: 48.9 %

Procedure:
3.7 g (10 mmoles) of (±)-3-acetyl-4,5-dihydro-8-chloro-4-methyl-1-(3-methyl4-nitrophenyl)-3H-2,3-benzodiazepine are dissolved in a mixture of 75 cm3 of methanol and 38 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is purified by chromatography over a column containing silica gel and using a mixture of ethyl acetate and hexane, then the product is recrystallized from ethanol. Thus, 1.67 g (49%) of the title compound are obtained in the form of pale yellow solids melting at 180–182° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][OH:10].[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[N:13]=[CH:14][CH:15]=[N:11]2)=[C:3]([CH2:9][OH:10])[CH:4]=1
Reactant: Cc1ccc(I)c(CO)c1
Reactant: c1c[nH]nn1
Product: Cc1ccc(-n2nccn2)c(CO)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for building block K11 from (2-iodo-5-methylphenyl)methanol [220991-50-4] and 1H-1,2,3-triazole.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:5]2[C:4]([NH2:15])=[N:3]1.O=[CH:17][C:18]([OH:20])=[O:19].[BH3-]C#N.[Na+]>CO>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=[C:5]2[C:4]([NH:15][CH2:17][C:18]([OH:20])=[O:19])=[N:3]1
Reactant: O=CC(=O)O
Reactant: Cn1nc(N)c2cc(C(F)(F)F)cnc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cn1nc(NCC(=O)O)c2cc(C(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 1-methyl-5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine (as prepared in the previous step, 284 mg, 1.31 mmol) in MeOH (20 mL), 2-oxoacetic acid (184 mg, 1.577 mmol) and NaBH3CN (86 mg, 1.37 mmol). The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. After flash chromatography (silica gel, ethyl acetate) the title compound was isolated as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[C:11]([CH3:19])[N:10]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH2:32])[CH:21]=1>CN(C=O)C>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:11]([CH3:19])[N:10]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: NCCOCCCc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.6 %

Procedure:
Under a nitrogen atmosphere, triethylamine (6.1 mL, 44 mmol) was added to a solution of 2,4-dichloro-6-methyl-3-nitropyridine (7.50 g, 36.2 mmol), prepared as described in Part A of Example 1, in anhydrous DMF (160 mL). Neat 2-[3-(pyridin-3-yl)propoxy]ethylamine (6.60 g, 36.6 mmol) was then added, and the mixture was stirred at room temperature for 1.5 hours. The volatiles were then removed under reduced pressure, and the residue was dissolved in chloroform. The solution was washed with 2% aqueous potassium bicarbonate (1×), water (1×), and brine (1×), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide an oil. The crude product was purified by column chromatography on silica gel (600 g, eluting with methanol:ethyl acetate in various ratios) to afford an oil which was dried under reduced pressure to yield 4.9 g of (2-chloro-6-methyl-3-nitropyridin-4-yl)-{2-[3-(pyridin-3-yl)propoxy]ethyl}amine.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[CH3:13]S(C)=O.CI.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH3:13])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)c(F)cc2o1
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: Cn1c(=O)oc2cc(F)c(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with 5-bromo-6-fluorobenzo[d]oxazol-2(3H)-one (3.6 g, 14.74 mmol) and DMSO (150 mL), and MeI (4.18 g, 29.5 mmol) and potassium carbonate (5.09 g, 36.9 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was poured to water (1.2 L) and the precipitate was filtered, washed with water and dried under high vacuum at 60° C. for 1 h to give 5-bromo-6-fluoro-3-methylbenzo[d]oxazol-2(3H)-one. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.32 (s, 3H) 7.62 (d, J=8.34 Hz, 1H) 7.70 (d, J=6.06 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])[CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccn2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 101 mg of 4-methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.75 (s, 3H), 6.76 (m, 2H, 7.45 (m, 2H), 7.63 (m, 2H), 7.71 (d, 1H, J=8.8 Hz), 7.78 (m, 1H), 7.88 (m, 2H), 8.64 (m, 1H), 10.24 (s, 1H). MS: m/z 403.9 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C@H:17]([N:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C@@H:20]3[CH3:32])[CH3:18])=[CH:13][C:12]=2[C:33]2[N:41]=[C:40]([CH3:42])[N:39]=[C:38]3[C:34]=2[N:35]=[CH:36][N:37]3C2CCCCO2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)C(O)=O.F[C:57](F)(F)[S:58](O)(=[O:60])=[O:59].CS(Cl)(=O)=O>C(Cl)Cl.O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:12]([C:33]3[N:41]=[C:40]([CH3:42])[N:39]=[C:38]4[C:34]=3[N:35]=[CH:36][NH:37]4)=[CH:13][C:14]([C@H:17]([N:19]3[CH2:24][CH2:23][N:22]([S:58]([CH3:57])(=[O:60])=[O:59])[CH2:21][C@@H:20]3[CH3:32])[CH3:18])=[CH:15][N:16]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ncc(Nc2ncc([C@@H](C)N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cc1F
Reactant: O=S(=O)(O)C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc([C@@H](C)N3CCN(S(C)(=O)=O)C[C@@H]3C)cc2-c2nc(C)nc3[nH]cnc23)cc1F
Reaction time: 1 h
Yield: 4.63 %

Procedure:
A mixture of (3S)-tert-butyl 4-((1R)-1-(6-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.180 g, 0.272 mmol) and trifluoroacetic acid (0.314 mL, 4.08 mmol) in DCM (10 mL) was treated with trifluoromethanesulfonic acid (0.01 mL) and allowed to stir under inert atmosphere for 1 h. The mixture was concentrated in vacuo, then THF (10 mL) was added to the residue and stirred 5 min. Then sodium carbonate (0.500 g) was added to the mixture and allowed to stir under inert atmosphere an additional 5 min. Then methanesulfonyl chloride (0.064 mL, 0.816 mmol) was added slowly via syringe into the mixture. The mixture was allowed to stir under inert atmosphere overnight. The mixture was diluted with DCM (20 mL),water (20 mL) and brine solution (10 mL). The organic layer was extracted with DCM (3×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was recrystallized from methanol and dichloromethane to give N-(5-fluoro-6-methoxypyridin-3-yl)-5-((R)-1-((S)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)ethyl)-3-(2-methyl-9H-purin-6-yl)pyridin-2-amine (0.007 g, 0.013 mmol, 4.63% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 12.69 (s, 1H) 9.84 (s, 1H) 8.38 (dd, J=12.42, 2.05 Hz, 1H) 8.28 (d, J=2.15 Hz, 1H) 8.22 (s, 1H) 8.11 (d, J=2.15 Hz, 1H) 7.26 (s, 8H) 4.16 (dq, J=14.18, 6.94 Hz, 1H) 4.04 (s, 3H) 3.30 (s, 2H) 3.14-3.21 (m, 1H) 2.93-3.06 (m, 4H) 2.85 (dd, J=10.76, 7.24 Hz, 1H) 2.69-2.78 (m, 4H) 2.55-2.64 (m, 1H) 1.54 (d, J=6.85 Hz, 3H) 1.13-1.32 (m, 3H). m/z (ESI, +ve ion) 556.1 (M+H)+.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N:12]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(C1CCCCC1=O)(=O)C>CN(C=O)C.[Cu](I)I>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:15]2[CH2:16][CH2:17][CH2:18][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:14]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: I[Cu]I
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 13.2 %

Procedure:
Methyl 4-iodobenzoate (1.00 g, 3.82 mmol, 1.0 eq) was dissolved in DMF and tert-butyl 1,4-diazepane-1-carboxylate (765 mg, 3.82 mmol, 1.0 eq), caesium carbonate (2.49 g, 7.63 mmol, 2.0 eq), 2-acetylcyclohexanone (101 μl, 0.76 mmol, 0.20 eq [20 mol %]) and copper iodide (37 mg, 0.19 mmol, 0.05 eq [5 mol %]) were added. The reaction mixture was stirred at 90° C. under nitrogen for 7 h. The reaction mixture was evaporated, dissolved in DCM (50 ml), washed with water (20 ml), saturated ammonium chloride solution (20 ml), dried over MgSO4, filtered and evaporated. The crude product was purified by silica column chromatography, eluting with 0-1% MeOH in DCM. The product containing fractions were combined, evaporated and dried in vacuo to give tert-butyl 4-(4-methoxycarbonylphenyl)-1,4-diazepane-1-carboxylate (168 mg, 13%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>>[Br:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[N:5]=[C:4]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(n1)[nH]c1ccccc12
Product: CC(C)(C)C(=O)Nc1nc(Nc2cccc(Br)c2)c2c(n1)[nH]c1ccccc12
Reaction time: 26 h
Yield: 80.8 %

Procedure:
Using the general procedure described above, the reaction of 6 (181 mg, 0.59 mmol) and 3-bromoaniline (771 mg, 4.48 mmol), was run for 26 hours, to provide 209 mg of 7 as a white solid in 80% yield. TLC Rf 0.28 (chloroform-methanol 20:1); mp 286.7-287.5° C.; 1H NMR (DMSO-d6) δ 1.27 (s, 9H, C(CH3)3), 7.19-7.49 (m, 4H, Ar—H), 8.18-8.46 (m, 4H, Ar—H), 8.79 (s, 1H, 4-NH, exch), 9.64 (s, 1H, 2-NH, exch), 11.89 (s, 1H, 9-NH, exch). Anal. Calculated (C21H20BrN5O): C, 57.54; H, 4.59; N, 15.97; Br, 18.22. Found: C, 57.34; H, 4.65; N, 15.80; Br, 17.96.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[F:11][C:12]1[C:17]([Sn](CCCC)(CCCC)CCCC)=[N:16][CH:15]=[CH:14][N:13]=1>C1(C)C=CC=CC=1.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:11][C:12]1[C:17]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=2)=[N:16][CH:15]=[CH:14][N:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccnc1F
Reactant: CSc1nc(C)nc(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CSc1nc(C)nc(-c2nccnc2F)n1
Temperature: 110 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
A mixture of 2-iodo-4-methyl-6-(methylthio)-1,3,5-triazine (100 mg, 0.374 mmol), 2-fluoro-3-(tributylstannyl)pyrazine (145 mg, 0.374 mmol) and tetrakis(triphenylphosphine)palladium(0) (43.3 mg, 0.037 mmol) in toluene (2 mL) was stirred at 110° C. for 18 h. The mixture was cooled down to room temperature. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give 2-(3-fluoropyrazin-2-yl)-4-methyl-6-(methylthio)-1,3,5-triazine (42 mg, 0.177 mmol, 47.3% yield). 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H); 8.42 (s, 1H); 2.73 (s, 3H); 2.65 (s, 3H). m/z (ESI, +ve ion) 238.0 (M+H)+.
Reaction SMILES: Cl[O-].[Na+].[C:4]([O:8][CH2:9][C:10](=[O:13])[CH2:11][F:12])([CH3:7])([CH3:6])[CH3:5].[C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH3:15].C(NC(C)C)(C)C.[Li]>>[C:18]([O:17][C:14](=[O:16])[CH2:15][C:10]([CH2:9][O:8][C:4]([CH3:7])([CH3:6])[CH3:5])([OH:13])[CH2:11][F:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OCC(=O)CF
Agent: [Li]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OCC(O)(CF)CC(=O)OC(C)(C)C

Procedure:
Starting from 2-tert-butoxymethyl-oxirane (5), 4-fluoromethyl-5H-furan-2-one can be prepared according to the method described in scheme 2. In the first step, the oxirane ring is opened with potassium hydrogendifluoride to form 1-tert-butoxy-3-fluoro-propan-2-ol (6) which is then oxidized to the corresponding ketone (7). The oxidation can be carried out according to known methods such as e.g. with sodium hypochlorite in the presence of a catalyst such as 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO). In a next step 1-tert-butoxy-3-fluoro-propan-2-one (7) is reacted with tert-butyl acetate in the presence of a strong base such as lithium diisopropylamine (LDA) to form 3-tert-butoxymethyl-4-fluoro-3-hydroxybutyric acid tert-butyl ester (8) which can be cyclizised to 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9) under strong acidic conditions (e.g. by employing trifluoroacetic acid or sulfuric acid 95%). Preferably, the cyclization is carried out with only a small amount of sulfuric acid 95% (e.g. 0.025 mol equivalent in relation to the educt) in a solvent such as 1,2-dimethoxyethane or dioxane. These two last steps can alternatively be carried out in a one-pot procedure, e.g. without isolating 3-tert-butoxymethyl-4-fluoro-3-hydroxybutyric acid tert-butyl ester (8). In a final step 4-fluoromethyl-5H-furan-2-one (III) is obtained by dehydration of 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9). The dehydration can be performed according to known methods, e.g with acetic anhydride in the presence of an amine base such as triethylamine. Alternative dehydration methods include the use of thionyl chloride in the presence of pyridine or mesyl chloride in the presence of triethylamine. In a further alternative dehydration method, 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one (9) is reacted with acetic anhydride to form the intermediate 4-acetoxy-fluoromethyl-dihydro-furan-2-one which is then reacted with sodium acetate in de-ionized water to obtain the compound of formula III.
Reaction SMILES: C(=O)C(C)C.[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.N1C[CH:35]=[C:34]([C:37]2C=CC(NC(N3CC4C(=CC=CC=4)C3)=O)=CC=2)[CH2:33][CH2:32]1>>[CH3:35][CH:34]([CH3:37])[CH2:33][CH2:32][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: O=C(Nc1ccc(OC2CCNCC2)cc1)N1Cc2ccncc2C1
Agent: CC(C)C=O
Product: CC(C)CCN1CCC(Oc2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 429, substituting 3-methylbutanal for isobutyraldehyde and N-(4-(piperidin-4-yloxy)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, Pyridine-d5. Temp=90° C.) δ ppm 8.53-8.57 (m, 2H) 8.09 (s, 1H) 7.70-7.78 (m, 2H) 7.10 (d, J=5.19 Hz, 1H) 6.98-7.04 (m, 2H) 4.79-4.89 (m, 4H) 4.26 (d, J=3.66 Hz, 1H) 2.72-2.83 (m, 2H) 2.34-2.41 (m, 2H) 2.21-2.30 (m, 2H) 1.96-2.03 (m, 2H) 1.79-1.91 (m, 2H) 1.54-1.68 (m, 1H) 1.35-1.44 (m, 2H) 0.86-0.90 (m, 6H); MS (APCI(+)) m/e 408 (M+H)+.