Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:23])[C:12]=2[C:13]2[S:22][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>O1CCCC1.C(Cl)Cl>[NH2:21][C:20]1[C:15]2[CH:14]=[C:13]([C:12]3[N:11]([CH3:23])[CH:10]=[N:9][C:8]=3[C:4]3[CH:3]=[C:2]([NH:1][C:32]([NH:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])=[O:33])[CH:7]=[CH:6][CH:5]=3)[S:22][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Reactant: O=C=Nc1ccccc1F
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cnc(-c2cccc(NC(=O)Nc3ccccc3F)c2)c1-c1cc2c(N)ncnc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
6-[4-(3-Aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (64 mg) in anhydrous tetrahydrofuran (10 mL) was added to 2-fluorophenyl isocyanate (34 mg) and stirred under an inert atmosphere at ambient temperature for 1 hr. The mixture was diluted with DCM (5 mL) then purified by chromatography on silica eluting with a gradient of 0-50% EtOAc/DCM, then 0-50% MeOH (containing 1% concentrated aqueous amnmonia)/DCM to give the title compound as a solid (76 mg, 82%).
Reaction SMILES: Cl[CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4].[C:9]([S-:11])#[N:10].[Na+]>CC(CC)=O>[S:11]([CH:2]([CH2:6][CH2:7][Cl:8])[C:3](=[O:5])[CH3:4])[C:9]#[N:10]
Reactant: N#C[S-]
Reactant: CC(=O)C(Cl)CCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: CC(=O)C(CCCl)SC#N
Yield: 96.3 %

Procedure:
A solution of 155.5 g (1 mole) of 3,5-dichloro-2-pentanone with 83 g (1.024 moles) of sodium rhodanide in 1 liter of methyl-ethyl-ketone is boiled for 1 hour under stirring. Then the procedure described in Example 1 is followed. 171 g (96.2%) of 3-thiocyanato-5-chloro-2-pentanone are obtained, which after distillation identical in all respect with the product of Example 1.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])O.[Na+].Br[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]=[CH:28]1>CN(C)C=O>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:32]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]2)[CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Reactant: BrC1C=CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(C2C=CCCC2)c2ccccc2NC1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of (±)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (28.6 g) in N,N-dimethylformamide (50 mL), sodium hydrogencarbonate (17.3 g) and 3-bromocyclohexene (33.2 g) were added, followed by LZ stirring at 50° C. for 1 hour. The reaction mixture was allowed to cool down. Subsequent to addition of ice water, the reaction mixture was extracted with methylene chloride. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue for crystallization. Crystals so precipitated were then collected by filtration. The crystals were washed with ethanol and then dried, whereby the title compound (30.1 g) was obtained. Yield: 82%.
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:23]C)[N:13]2[CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:9]([NH2:25])[N:8]=1)[CH2:3][CH2:4][CH3:5].Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: CCCC(C)Oc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCC(C)Oc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
To a solution of 2-[(1-methylbutyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (92 mg) in dry MeOH (9.9 mL) was added 4N HCl in 1,4-dioxane (1.7 mL) and the reaction mixture was stirred at room temperature for 3 h. The reaction was neutralised to pH7 with 2M sodium hydroxide solution and concentrated in vacuo to give an off-white solid. The solid was triturated with water (30 mL) and filtered under reduced pressure to give the title compound as an off-white solid (55 mg).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[N:25][CH:24]=[CH:23]2>>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)[CH:23]=[CH:24][N:25]=1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: Nc1cccc2ccncc12
Agent: [I-]
Product: c1ccc2c(c1)C[C@H]1CSC(=Nc3cccc4ccncc34)N1C2
Yield: 71.1 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.2 g) and 8-aminoisoquinoline (10.9 g) as the starting materials, (S)-3-(isoquinol-8-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (11.8 g) is obtained in the form of pale yellow crystals, m.p.=206° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N2CN3CN(C2)C[N:20]1C3.C(O)C.Cl>C(Cl)(Cl)Cl>[NH2:20][CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)=[O:18]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CCl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NCC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
78 g of 1-(4-benzyloxyphenyl)-2-chloroethanone and 63 g of hexamine are dissolved in 2.2 liters of chloroform, and the mixture is stirred at room temperature overnight. The mixture is condensed to a volume of 1.1 liters, and refluxed for 3 hours. After cooling, the precipitated crystals are collected by filtration, washed and then dried. The colorless crystals thus obtained are added to a mixture of 750 ml of ethanol and 120 ml of conc. hydrochloric acid, and the mixture is refluxed for 50 minutes. After cooling, the precipitated crystals are collected by filteration, washed and then dried. 55.6 g of 2-amino-1-(4-benzyloxyphenyl)ethanone are obtained as colorless crystals.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[CH:9][CH:8]=1.[CH3:18][C:19]1([CH3:36])[CH2:28][C:27](=O)[C:26]2[C:21](=[CH:22][C:23]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[CH:24][CH:25]=2)[O:20]1>O1CCCC1.CCOCC>[CH3:18][C:19]1([CH3:36])[CH:28]=[C:27]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[CH:9][CH:8]=2)[C:26]2[C:21](=[CH:22][C:23]([O:30][CH2:31][CH2:32][N:33]([CH3:34])[CH3:35])=[CH:24][CH:25]=2)[O:20]1
Reactant: Cc1ccc(Br)c2ccccc12
Reactant: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C2=CC(C)(C)Oc3cc(OCCN(C)C)ccc32)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of butyl lithium (12.5 ml, 0.03 mole, 2.4M solution in hexane) was added dropwise over 20 minutes a solution of 1-bromo-4-methylnaphthalene (6.63 g, 0.03 mole) in dry tetrahydrofuran (10 ml), the reaction mixture being cooled throughout by a water bath. After being stirred at ambient temperature for 15 minutes the resulting suspension was treated with a solution of 2,2-dimethyl-7-(2-dimethylaminoethoxy)-4-chromanone (4.0 g, ~0.015 mole) in dry tetrahydrofuran (15 ml), the precipitate almost immediately dissolving to give a golden yellow solution. The resulting solution was stirred under reflux for 5 hours, then left overnight at ambient temperature, stirred under reflux for a further 7 hours and again left overnight at ambient temperature. After work up with acid, by an analogous process to that described in Example 1 and chromatography on alumina in 8% ether - 92% petroleum ether (b.p. 60°-80°) the title compound was obtained as a colourless oil (0.65 g, 11%). Its hydrochloride salt was m.p. 215°-216.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([OH:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([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.N1C=CN=C1.Cl>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[CH:10]([O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:3]=1
Reactant: CCCCCCCCC(O)/C=C/c1cccc(Br)n1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCCC(/C=C/c1cccc(Br)n1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
A solution of 4 g of 2-bromo-6-[(1E)-(3RS)-3-hydroxy-1undecenyl]-pyridine in 20 ml of dimethylformamide is mixed with 4.1 g of tert-butyldiphenylsilyl chloride and 2.1 g of imidazole and stirred for 15 hours at room temperature. The reaction mixture is poured into 100 ml of diethyl ether, shaken out twice with 20 ml of 1 n hydrochloric acid, 4 times with 20 ml of saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/0-5% ethyl acetate. 5.5 g of 2-bromo-6[(1E)-(3RS)-3-tert-butyldiphenylsilyloxy-1-undecenyl]-pyridine is obtained as oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[N:7]2[CH2:13][CH:14]=O.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[N:7]2[CH2:13][CH2:14][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]1
Reactant: O=CCn1c(=O)ccc2c(F)cc(F)cc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
(5,7-Difluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (2.1 g; 9.4 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (2.82 g; 14.1 mmol) were dissolved in a 1:1 mixture of chloroform and MeOH (60 ml:60 ml) and stirred at rt for 1 h. This was then treated with NaBH(OAc)3 (8.92 g; 42.3 mmol) and stirred for a further 1 h. More 1,1-dimethylethyl 4-piperidinylcarbamate (470 mg; 2.35 mmol) was added and the reaction stirred under the same conditions for 20 mins, this was then treated with NaBH(OAc)3 (1.98 g; 9.4 mmol) and stirred for 25 mins. More 1,1-dimethylethyl 4-piperidinylcarbamate (470 mg; 2.35 mmol) was then added and the reaction stirred for 20 mins. More NaBH(OAc)3 (500 mg; 2.38 mmol) was then added to the reaction and it was stirred overnight at rt. The solvents were then removed and the crude residue purified by column chromatography on silica gel using a 0-15% MeOH/DCM gradient to give the desired product (2 g; 52%).
Reaction SMILES: [C:1]([N:4]([C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([Br:17])=[CH:10][C:9]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C(=O)C)(=[O:3])[CH3:2].C.O.NN>CO.[Fe](Cl)(Cl)Cl>[NH2:14][C:13]1[CH:12]=[C:11]([Br:17])[CH:10]=[C:9]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)c1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CC(=O)Nc1c(N)cc(Br)cc1OCc1ccccc1
Yield: 65.5 %

Procedure:
A suspension of 23 g (56 mmol) N-acetyl-N-(2-benzyloxy4-bromo-6-nitro-phenyl)-acetamide, 5.5 g (34 mmol) iron(III) chloride and 13.8 g activated charcoal in 600 ml methanol was heated to reflux. To the reaction mixture were added 28 ml hydrazine hydrate (95%) to maintain gentie reflux. After complete reaction (2 h), the reaction mixture was cooled down and filtered through celite. The filter cake was washed thoroughly with dichloromethane/methanol and the filtrate was evaporated to dryness. The residue was partitioned between dichloromethane/methanol and water. The organic layer was washed with brine, dried over anhydrous magnesium sulphate and evaporated. The residue was recrystallized from boiling ethyl acetate/n-heptane to give 12.3 g (65%) of the title compound as a colourless solid. m.p. 185° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH3:10])[C:3]=1[C:20]([O:22]C)=O.[O:24]1[CH2:29][CH2:28][CH2:27][CH:26]([NH2:30])[CH2:25]1.Cl>>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([NH:7][C:8](=[O:19])[C@@H:9]([NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:10])[C:3]=1[C:20](=[O:22])[NH:30][CH:26]1[CH2:27][CH2:28][CH2:29][O:24][CH2:25]1
Reactant: NC1CCCOC1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)NC1CCCOC1

Procedure:
Same procedure as described in preparation 137a was used from (S)-methyl 3-bromo-1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (4.00 g, 10.25 mmols) and tetrahydro-2H-pyran-3-amine.HCl (2.12 g, 15.41 mmols). The title compound was obtained (2.24 g, 48%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=O)[CH:27]=[N:28][C:29]=1[CH2:30][OH:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCl.CO>[Cl:23][C:24]1[CH:25]=[C:26]([CH2:32][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:22])[CH2:6][CH2:7]2)[CH:27]=[N:28][C:29]=1[CH2:30][OH:31]
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cnc(CO)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cnc(CO)c(Cl)c4)CC3)c2c1
Reaction time: 3 h
Yield: 29.7 %

Procedure:
1-[2-(4-amino-1-piperidinyl)ethyl]-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (Intermediate 29: 100 mg, 0.331 mmol) was dissolved in a mixture of Dichloromethane (DCM) (4 mL) and Methanol (0.444 mL). Aldehyde 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (Intermediate 39: 56.7 mg, 0.331 mmol) was added and the mixture was left at room temp. for 3 hours. Then sodium triacetoxy borohydride (210 mg, 0.992 mmol) was added and after 2 hours 2 more eq. of triacetoxy borohydride were added leaving the reaction under stirring overnight. LCMS overnight showed still imine remaining so 3 eq more of sodium triacetoxy borohydride were added and 2 eq more after 3 hours leaving the reaction overnight. Next morning 2 more eq. of sodium triacetoxy borohydride were added and after 3H reaction was stopped. Volatiles were removed under vacuum and the corresponding crude was diluted with DCM and washed with NaHCO3 several times. Organic layers were dried over Na2SO4, filtered and volatiles removed under vacuum. Corresponding crude was purified by flash master chromatography. Si II, 5 g. DCM/MeOH (0-30%), to obtain a solid which was left in the oven overnight to afford 45 mg of the final compound as a pale yellow solid.
Reaction SMILES: Cl.[CH:2]([NH:5][OH:6])([CH3:4])[CH3:3].C(OCC)C.[OH-].[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:26]=[C:27]=[O:28])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>O>[OH:6][N:5]([CH:2]([CH3:4])[CH3:3])[C:27]([NH:26][C:18]1[CH:17]=[C:16]([O:15][CH3:14])[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:28]
Reactant: CC(C)NO
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1cc(NC(=O)N(O)C(C)C)cc(OC)c1OC
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
A solution of N-isopropylhydroxylamine hydrochloride (1.2 g, 11 mmol) in water (5 mL) was combined with diethyl ether (35 mL) then cooled in an ice bath. A solution of sodium hydroxide (0.5 g, 12.5 mmol) in water (7 mL) was added over a 10 minute period. The reaction mixture was stirred for 10 minutes then 3,4,5-trimethoxyphenyl isocyanate (2.1 g, 10 mmol) was added as a solid. The reaction mixture was stirred at ambient temperature for 18 hours then filtered to remove a white precipitate. The filtrate was concentrated under vacuum to provide 2.1 g of the desired product as a white solid. An analytical sample was prepared by recrystallization from hexanes:ethyl acetate, m.p. 140.0°-141.0 ° C. Analysis: Calculated for C13H20N2O5 : %C, 54.92; %H, 7.09; %N, 9.85; Found: %C, 55.12; %H, 7.06; %N, 9.77.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:11]=[C:10]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[O:21]=[C:22]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][CH:32]=O)=[CH:30][C:25]=2[CH2:24][O:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:11]=[C:10]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:32][CH2:31][C:29]3[CH:28]=[CH:27][C:26]4[C:22](=[O:21])[O:23][CH2:24][C:25]=4[CH:30]=3)[CH2:16][CH2:15]2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: N#Cc1ccc(CCN2CCNCC2)cc1OC(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)cc1OC(F)F

Procedure:
A solution of crude 2-(difluoromethoxy)-4-(2-piperazin-1-ylethyl)benzonitrile (15 mg, 0.05 mmol), (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde (18 mg, 0.1 mmol) and NaBH(OAc)3 (100 mg, 0.47 mmol) in 10 mL of anhydrous DCM was stirred at ambient temperature overnight. The reaction mixture was added 50 mL of DCM, washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with prep-TLC to afford 2-(difluoromethoxy)-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (400 MHz, CDCl3) δ 7.82 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.33˜7.36 (m, 2H), 7.13˜7.20 (m, 2H), 6.33 (t, J=71.2 Hz, 1H), 5.26 (s, 2H), 2.99˜3.08 (m, 2H), 2.87˜2.90 (m, 2H), 2.62˜2.84 (m, 12H). (0.15 μm)
Reaction SMILES: [F:1][C:2]1[C:3]([C:14](Cl)=[N:15][OH:16])=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[C:20]=1[Cl:32]>CN(C=O)C>[F:1][C:2]1[C:3]([C:14]2[CH2:26][C:25]([C:23]3[CH:22]=[C:21]([Cl:31])[C:20]([Cl:32])=[C:19]([Cl:18])[CH:24]=3)([C:27]([F:30])([F:29])[F:28])[O:16][N:15]=2)=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: CC1(C)OB(O)c2cc(F)c(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2cc(F)c(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of the crude compound 6-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (310 mg, 0.95 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (262 mg, 0.95 mmol) in DMF (5 mL) at rt was added TEA (158 μL, 1.2 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with DCM (60 mL×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 6-fluoro-3,3-dimethyl-5-(5-(3,4,5-trichloro-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (86 mg; yield 16% over 3 steps from the aldehyde) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.352 (s, 1H), 7.875 (s, 2H), 7.826 (d, J=6.0 Hz, 1H), 7.513 (d, J=10.0 Hz, 1H), 4.399 (d, J=18.5 Hz, 1H), 4.274 (d, J=18.5 Hz, 1H), 1.482 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=495.9 (M+1, ESI+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>C(O)CCC>[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: NCCCCCN
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NCCCCCNc1nc(Cl)nc2[nH]ccc12
Yield: 84.1 %

Procedure:
A solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (70 mg, 0.37 mmol), 1,5-diaminopentane (0.130 mL, 1.11 mmol) and triethylamine (0.150 mL, 1.08 mmol) in nBuOH (3 mL) was stirred at 70° C. for 1 h. It was then purified by HPLC to give N-(5-aminopentyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a solid (79 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH3:9].CCN(CC)CC.[F:17][C:18]1([F:33])[O:22][C:21]2[CH:23]=[CH:24][C:25]([C:27]3([C:30](Cl)=[O:31])[CH2:29][CH2:28]3)=[CH:26][C:20]=2[O:19]1>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:30]([C:27]2([C:25]3[CH:24]=[CH:23][C:21]4[O:22][C:18]([F:33])([F:17])[O:19][C:20]=4[CH:26]=3)[CH2:29][CH2:28]2)=[O:31])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Cc1ccc(N)nc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of 6-chloro-5-methylpyridin-2-amine (11.1 g, 78.0 mmol) and Et3N (22.0 mL, 156 mmol) in dichloromethane (100 mL) was added a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (20.3 g, 78.0 mmol) in dichloromethane (50 mL). The resulting reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was then washed with 1N aqueous NaOH (2×200 mL), 1 N aqueous HCl (1×200 mL), and saturated aqueous NaHCO3 (1×200 mL). The organics were dried over sodium sulfate and evaporated to yield N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (26.9 g, 94%). ESI-MS m/z calc. 366.1. found 367.3 (M+1)+. Retention time 2.19 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.89-7.87 (m, 1H), 7.78-7.76 (m, 1H), 7.54-7.53 (m, 1H), 7.41-7.39 (m, 1H), 7.33-7.30 (m, 1H), 2.26 (s, 3H), 1.52-1.49 (m, 2H), 1.19-1.16 (m, 2H).
Reaction SMILES: [C:1]([CH:3]([C:9]([C:11]1[C:12]2[CH2:25][O:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[C:13]=2[N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1)=[O:10])[C:4](OCC)=[O:5])#[N:2].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C(C)=CC=CC=1>[C:1]([CH:3]([C:9]([C:11]1[C:12]2[CH2:25][O:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[C:13]=2[N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1)=[O:10])[C:4]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:5])#[N:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C(C#N)C(=O)c1nn(-c2ccccc2)c2c1COc1ccccc1-2
Solvent: Cc1ccccc1C
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1COc1ccccc1-2
Yield: 52 %

Procedure:
2-Cyano-3-(1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanoic acid, ethyl ester (1.2 g) is reacted with aniline (1.1 g) in xylene (100 ml) at the reflux temperature for 48 hours. After cooling the precipitate is filtered and washed with xylene, then crystallized from dichloromethane/methanol to give 0.7 g of 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 280°-282° C.