Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N+:10]=1[O-])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:20]C(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:10]=1)(=[O:19])[CH3:18]
Reactant: Cc1cccc(OCc2ccccc2)[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1cccc(OCc2ccccc2)n1

Procedure:
A mixture of 2-benzyloxy-6-methylpyridine N-oxide (3.4 g, 15.9 mmol) and acetic anhydride (125 mL) was heated under reflux for 1 h. The resulting solution was concentrated under vacuum, and the residue was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 10-20% ethyl acetate in hexane gradient. Collection and concentration of appropriate fractions provided 2-acetoxymethyl-6-benzyloxypyridine as colorless oil.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:13]2[CH:25]=1.O>CS(C)=O>[CH3:9][C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3[CH2:4][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:13]2[CH:25]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cccc2nc(C)cn12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC1c1cccc2nc(C)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a suspension of 60% sodium hydride (1.10 g, 25.3 mmol) in dimethyl sulfoxide (50 mL) was added trimethylsulfoxonium iodide (5.56 g, 25.3 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methylimidazo[1,2-a]pyridin-5-yl)acrylate (4.85 g, 21.1 mmol) in dimethyl sulfoxide (100 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=33/67) to give the title compound (3.40 g, yield 66%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].CS(O[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:14]([O:48][CH3:49])=[N:15][C:16](/[C:19](/[C:38]2[CH:43]=[CH:42][C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:40][CH:39]=2)=[CH:20]/[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[O:36][CH3:37])=[CH:17][CH:18]=1)(=O)=O>>[C:44]([C:41]1[CH:40]=[CH:39][C:38](/[C:19](/[C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:2]([CH3:3])[CH3:1])=[C:14]([O:48][CH3:49])[N:15]=2)=[CH:20]\[C@@H:21]2[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH3:37])[C:23](=[O:26])[CH2:24][CH2:25]2)=[CH:43][CH:42]=1)([CH3:47])([CH3:46])[CH3:45]
Reactant: CNC
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCOS(C)(=O)=O)c(OC)n2)c(OC)c1
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCN(C)C)c(OC)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Triethylamine (50 μL) and methanesulfonyl chloride (25 μL) were added to a solution of (5R)-5-{(E)-2-(4-tert-butylphenyl)-2-[5-(4-hydroxybutyl)-6-methoxypyridin-2-yl]ethenyl}-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (144 mg) in chloroform (2 mL), and the mixture was stirred at room temperature for three hours. Triethylamine (50 μL) and methanesulfonyl chloride (25 μL) were further added thereto and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)butyl methanesulfonate as a crude product. 2 M dimethylamine (solution in methanol) (3 mL) was added to 4-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)butyl methanesulfonate, and the mixture was stirred at room temperature for 17 hours. The solvent was evaporated from the reaction solution and then water was added, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0→4:1) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-[4-(dimethylamino)butyl]-6-methoxypyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:22][SiH:23]([Cl:25])[Cl:24]>>[CH2:14]([Si:23]([Cl:25])([Cl:24])[Cl:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Product: Cl[Si](Cl)(Cl)Cc1ccccc1
Yield: 94.6 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 0.95 g (7.5 mmol) of benzyl chloride, and 5.08 g (37.5 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 1.6 g of benzyltrichlorosilane (bp; 140-2° C./10 mmHg, yield; 96%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:48][C@@H:49]1[CH2:54][CH2:53][CH2:52][CH2:51][C@H:50]1[OH:55]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:48][C@@H:49]1[CH2:54][CH2:53][CH2:52][CH2:51][C@H:50]1[OH:55])=[O:9]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (50.0 g, 0.166 mol) was dissolved in DMF (600 mL). To the solution was added TBTU (58.9 g, 0.183 mol), N,N-diisopropylethyl amine (142.6 mL, 0.83 mol) and (1R,2R)-2-amino-cyclohexanol (21.1 g, 0.183 mol). The reaction mixture was stirred for 3 h at room temperature. The solvent was evaporated in vacuo, the residue was dissolved in a mixture of ethyl acetate (1200 mL) and THF (300 mL). The solution was washed twice with water (700 mL) and the water phases were extracted with ethyl acetate (600 mL). Organic phases were pooled, dried with MgSO4 and concentrated to about 900 mL. The product precipitated upon stirring and cooling to 0° C. Filtration, washing with ethyl acetate/n-heptane (1:1) and drying in vacuo gave the title compound (53.1 g) as a white solid; MS (ISP) 397, 399 (M)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[C:33](Cl)(=[O:42])[CH:34]=[CH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:11]([CH3:32])[C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:33](=[O:42])/[CH:34]=[CH:35]/[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[S:3][C:4]=3[N:5]=2)[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)/C=C/c3ccccc3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 338 μmol) produced in Example D5(i) in pyridine (4 mL) was added cinnamoyl chloride (141 mg, 845 μmol), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20L, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=30/70→10/90), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (150 mg, 77%) as yellow crystals.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=O)=[O:9])[C:2]#[CH:3].[Na+].S(Cl)([Cl:15])=O>ClCCl>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][S:8]([Cl:15])(=[O:11])=[O:9])[C:2]#[CH:3]
Reactant: C#CCOCCCS(=O)(=O)[O-]
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOCCCS(=O)(=O)Cl
Yield: 95.6 %

Procedure:
Referring to FIG. 16, a slurry of sodium 3-(propargyloxy)propyl sulfonate (5.0 g, 25.0 mmol, 1.0 equiv.) and thionyl chloride (25 mL, 344 mmol, 13.8 equiv.) was heated to 100° C. under N2 for three hours. The mixture was concentrated to a thick oil, diluted with 50 mL benzene, and concentrated again by rotavap to obtain a waxy solid. The material was slurried in 50 mL dichloromethane and filtered. The solids were discarded and the mother liquor concentrated on rotavap to obtain product as an orange oil (4.7 g, 95%). 1H NMR (300 MHz, CDCl3) δ 4.17 (d, 2H), 3.82 (t, 2H), 3.70 (t, 2H), 2.47 (t, 1H), 2.34 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[C:8]=2[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].[CH3:20][NH2:21]>C(O)C>[CH3:20][NH:21][C:15](=[O:17])[CH2:14][C:9]1[C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cc1cccc2c(C(C)C)nccc12
Reactant: CN
Solvent: CCO
Product: CNC(=O)Cc1cccc2c(C(C)C)nccc12

Procedure:
Ethyl 1-isopropylisoquinoline-5-acetate (0.4 g) was dissolved in 20 ml of ethanol, and 5 ml of a 40% aqueous solution of monomethylamine was added. The mixture was stirred under heat for 12 hours. After the reaction, the solvent was distilled off. The residue was extracted with benzene, washed in water, and dried. The solvent was distilled off under reduced pressure. Recrystallization from benzenecyclohexane afforded 0.15 g of 1-isopropylisoquinoline-5-acetic acid methylamide as colorless needles having a melting point of 153.2° to 153.7° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[C:15]2/[C:16](=[O:32])[C:17]3[C:22]([CH2:23]/2)=[CH:21][C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[C:19]([O:30][CH3:31])[CH:18]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH:15]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:21]=3)[C:16]2=[O:32])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\C1CCN(Cc3ccccc3)CC1)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(CC1CCN(Cc3ccccc3)CC1)C2=O
Reaction time: 6 h

Procedure:
Compound 22 (85 mg, 0.195 mmol) was dissolved in methanol 25 mL, added Pd/C 40 mg and stirred under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude compound 23. The crude material was purified by flash chromatography using 100-200 mesh silica gel. The compound was eluted with 20% ethyl acetate in hexane to give half white coloured solid compound 2-((1-benzylpiperidin-4-yl)methyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 23. 1HNMR (400 MHz, CDCl3) δ ppm 7.31 (m, 5H), 7.15 (bs, 1H), 6.85 (bs, 1H), 3.88 (m, 7H), 3.51 (bs, 2H), 3.22 (m, 4H), 2.90 (m, 2H), 2.65 (m, 2H), 1.90 (m, 3H), 1.64 (m, 2H), 1.58 (bs, 4H); MS (ESI) m/z 435.2 (M+H).
Reaction SMILES: [CH2:1]([N:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(N(CC)CC)C.[Cu]I.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>[CH2:1]([N:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CN(Cc1ccccc1)C1(c2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)C1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Temperature: 70 °C
Yield: 85.7 %

Procedure:
Using General Procedure D; benzyl-[1-(4-bromophenyl)-cyclopropyl]-methylamine (Intermediate 130, 90.0 mg, 0.28 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (6.0 mg, 0.03 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (20.0 mg, 0.03 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound 80 mg (84%) was isolated by chromatography (0-2% EtOAc-hexanes).
Reaction SMILES: [I:1][C:2]1[C:7]([O:8]COC)=[CH:6][CH:5]=[CH:4][C:3]=1[O:12][CH3:13].Cl.C([O-])(O)=O.[Na+]>ClCCl>[I:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COCOc1cccc(OC)c1I
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(O)c1I
Yield: 74.8 %

Procedure:
To a solution of 2-iodo-1-(methyloxy)-3-{[(methyloxy)methyl]oxy}benzene (Intermediate 2, 16.2 g, 55.1 mmol) in dichloromethane (100 ml, SCRC) was bubbled HCl (g) for 30 mins. TLC showed that the reaction was completed. The reaction mixture was poured into an aqueous saturated solution of NaHCO3 (200 ml) and extracted with dichloromethane (3×200 ml, SCRC). The combined organic layers were dried, evaporated and purified by column chromatography on silica gel (EtOAc: PE=1:50) to afford the title compound as a yellow liquid (10.3 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[NH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:9]([O:8][CH2:7][CH:6]([NH:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)COC(C)=O
Reactant: CC(C)(C)OC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(=O)OCC(COC(C)=O)NCC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
To a solution of 3-(acetyloxy)-2-oxopropyl acetate (3.0 g, 17.24 mmol) on dichloroethane (70 ml) was added tert-butyl 2-aminoacetate (2.35 ml, 17.24 mmol). The reaction was stirred for 90 minutes before sodium triacetoxyborohydride (5.5 g, 25.86 mmol) was added and stirring was continued for 18 hours. The reaction was quenched by the addition of saturated sodium hydrogen carbonate solution and the crude product was extracted into dichloromethane. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with 0-40% EtOAc:Hept to yield the title compound (1.93 g, 38% yield). 1H NMR (250 MHz, CHLOROFORM-d) δ 3.96-4.26 (4H, m), 3.30-3.45 (2H, m), 3.06 (1H, quin, 5.4 Hz), 2.09 (6H, s), 1.47 (9H, s).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[N:29]=[CH:28][N:27](COCC[Si](C)(C)C)[N:26]=4)=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].C([C@H]1COC(=O)N1C1C=CN2N=CC(C3C=CC(C4N(COCC[Si](C)(C)C)N=CN=4)=CC=3)=C2N=1)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:27]1[CH:28]=[N:29][C:25]([C:22]2[CH:21]=[CH:20][C:19]([C:18]3[CH:17]=[N:16][N:13]4[CH:14]=[CH:15][C:10]([N:5]5[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]5=[O:9])=[N:11][C:12]=34)=[CH:24][CH:23]=2)=[N:26]1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Agent: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncnn4COCC[Si](C)(C)C)cc3)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
A mixture of (S)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (2.37 g, 4.25 mmol) was dissolved in dichloromethane (12 mL) and trifluoroacetic acid (22.5 mL) was added and the mixture allowed to stir at ambient temperature for 6 hours. The reaction mixture was concentrated and the residue partitioned between saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL). The aqueous layer was washed with EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to give a golden yellow solid. Purification of the crude material by column chromatography, eluting with a gradient of Hexanes to 50% EtOAc/Hexanes to 0-2% (9:1 MeOH/NH4OH)/EtOAc provided (S)-3-(3-(4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (1.30 g, 78%) as a yellow crystalline solid. LCMS (APCI+) m/z 390 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J=7.8 Hz, 1H), 8.77 (s, 1H), 8.37 (bs, 1H), 8.22 (d, J=8.6 Hz, 2H), 8.05 (d, J=8.6 Hz, 2H), 7.89 (d, J=7.4 Hz, 1H), 4.95-4.99 (m, 1H), 4.52 (d, J=6.2 Hz, 2H), 2.74-2.82 (m, 1H), 1.07 (d, J=7.0 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([NH:7][C:8]1[CH:9]=[N:10][C:11]([C:23]#[N:24])=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)[CH:13]=1)(=[O:6])=[O:5].[OH-:25].[K+].OO>CS(C)=O>[NH2:1][CH2:2][CH2:3][S:4]([NH:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)[C:11]([C:23]([NH2:24])=[O:25])=[N:10][CH:9]=1)(=[O:6])=[O:5]
Reactant: [OH-]
Reactant: Cc1cc(C)nc(Nc2cc(NS(=O)(=O)CCN)cnc2C#N)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C)nc(Nc2cc(NS(=O)(=O)CCN)cnc2C(N)=O)c1
Reaction time: 1 h

Procedure:
To a solution of 2-amino-N-{6-cyano-5-[(4,6-dimethylpyridin-2-yl)-amino]pyridin-3-yl}ethanesulfonamide (78 mg, 0.23 mmol) in DMSO (1.8 mL) was added potassium hydroxide (63 mg, 1.1 mmol) and hydrogen peroxide (35% w/w in water, 0.20 mL, 2.3 mmol). The reaction mixture was stirred for 1 hour. The reaction mixture was filtered and the filtrate directly purified by reverse phase HPLC to afford 5-{[(2-aminoethyl)sulfonyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide. MS ESI calc'd. for C15H21N6O3S [M+H]+ 365. found 365. 1H NMR (500 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.45 (d, J=2.3 Hz, 1H), 7.80 (s, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.12 (s, 1H), 6.51 (s, 1H), 6.47 (s, 1H), 2.92 (t, J=6.1 Hz, 2H), 2.89-2.81 (m, 2H), 2.32 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([NH:26][CH3:27])=[O:25])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(P(CCCC)CCCC)CCC.O[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]([CH3:27])[CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: OCc1ccccn1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CN(Cc1ccccn1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
1-1′-Azobis(N,N-dimethylformamide) (645 mg, 3.75 mmol) was added to a cooled solution of tert-butyl (3R)-6-cyclohexyl-3-{3-[(methylamino)carbonyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 7) (1.42 g, 3.75 mmol), tributylphosphine (930 μl, 3.75 mmol) and 2-hydroxymethylpyridine (240 μl, 2.50 mmol) in toluene (10 ml) and the resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 15 minutes, then at room temperature for 72 hours. The mixture was filtered and the solvent removed from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (90:10) gradually changing to hexane:ethyl acetate (50:50) to afford the title compound as a pale yellow oil (530 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:37]([O:39][CH:40]([CH3:42])[CH3:41])=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([O:8]CC1C=CC=CC=1)=[O:7])[CH3:2]>C(O)(C)C>[CH2:1]([O:3][C:4]1[CH:19]=[C:18]([CH2:20][C:21]([NH:23][CH:24]([C:37]([O:39][CH:40]([CH3:41])[CH3:42])=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:22])[CH:17]=[CH:16][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1cc(CC(=O)NC(C(=O)OC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)OCc1ccccc1
Solvent: CC(C)O
Product: CCOc1cc(CC(=O)NC(C(=O)OC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)O

Procedure:
Prepared analogously to Example 40 by catalytic hydrogenation of benzyl 2-ethoxy-4-[N-(α-isopropoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate in isopropanol.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(C(C)=O)C>[O:1]([CH2:8][CH2:9][CH2:10][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: ClCCCOc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: c1ccc(OCCCN2CCNCC2)cc1

Procedure:
A mixture of 3-phenoxy-1-chloro-propane (1 mole), sodium iodide (1 mole) and anhydrous piperazine (4 moles) is added to methyl ethyl ketone (1000 ml). The mixture is refluxed during 24 hours, with stirring. The solvent is removed in vacuo over a water-bath and the residue is poured over water. The aqueous phase is extracted with methylene chloride and then washed twice with water. The solvent is removed and the residual oil is distilled. B.p. = 115° C./0.05 mm Hg.
Reaction SMILES: [CH2:1]1[C@@:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=3)[C:17]2=[O:27])=[CH:12][CH:11]=1.Br[CH2:29][CH2:30][CH2:31][F:32].C(=O)([O-])O.[Na+].CN1C(=O)CCC1>O.C(OCC)(=O)C>[F:32][CH2:31][CH2:30][CH2:29][N:7]1[CH2:8][CH2:9][C@@:5]2([CH2:1][N:2]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:25][CH2:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=5)[C:17]4=[O:27])=[CH:12][CH:11]=3)[CH2:3][CH2:4]2)[CH2:6]1
Reactant: FCCCBr
Reactant: O=C1c2ccc(O)cc2CCN1c1ccc(N2CC[C@]3(CCNC3)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C1c2ccc(O)cc2CCN1c1ccc(N2CC[C@]3(CCN(CCCF)C3)C2)cc1
Temperature: 50 °C

Procedure:
A mixture of 2-[(S)-4-(2,7-diaza-spiro[4.4]non-2-yl)-phenyl]-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.20 g), 1-bromo-3-fluoro-propane (76 mg), sodium hydrogencarbonate (10 mg) and NMP (5 mL) was heated at 50° C. for 15 hours. The reaction mixture was distributed between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The raw product was purified by preparative HPLC. In this way the product was obtained with molecular weight 423.54 (C25H30FN3O2); MS (ESI): 424 (M+H+).