Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])=[CH:15][CH:14]=2)[N:3]=1.[C:26]([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH2:36])=[N:31]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH:36][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[N:4]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[CH:15][CH:14]=3)[N:3]=2)=[N:31]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1ccccc1-c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reactant: Cc1cc(N)nn1C(C)(C)C
Product: Cc1ccccc1-c1ccc(-n2nc(Nc3cc(C)n(C(C)(C)C)n3)c3ccccc3c2=O)cc1
Yield: 31 %

Procedure:
4-Bromo-2-(2′-methyl-biphenyl-4-yl)-2H-phtalazin-1-one (prepared from the appropriate starting materials in analogy to Method Q-1) was coupled with 1-tert-butyl-5-methyl-1H-pyrazol-3-ylamine in a Buchwald reaction as described in Method O to give the title compound (0.049 g, 31% yield). 1H-NMR: (400 MHz, D6-DMSO) 8.44 (1H, s), 8.40 (1H, d), 8.33 (1H, d), 8.05 (1 H, t), 7.97 (1H, t), 7.62 (2H, d), 7.40 (2H, d), 7.30 (2H, d), 7.24 (2H, d), 6.00 (1H, s), 2.28 (3H, s), 2.12 (3H, s), 1.57 (9H, s); MS (ESI+)=464.36 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9]([Cl:23])=[N:10][C:11]([S:21][CH3:22])=[N:12][C:13]=1[NH:14][CH:15]1[CH2:18][C:17]([F:20])([F:19])[CH2:16]1)(=O)=O.C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O>[Cl:23][C:9]1[C:8]2[CH2:7][CH2:6][N:14]([CH:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)[C:13]=2[N:12]=[C:11]([S:21][CH3:22])[N:10]=1
Reactant: CSc1nc(Cl)c(CCOS(C)(=O)=O)c(NC2CC(F)(F)C2)n1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2c(n1)N(C1CC(F)(F)C1)CC2
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 2-{4-chloro-6-[(3,3-difluorocyclobutyl)amino]-2-(methylsulfanyl)pyrimidin-5-yl}ethyl methanesulfonate (922 mg, 2.38 mmol) in DMF (23 mL) was added DBU (0.725 mL, 4.75 mmol). The mixture was stirred at 80° C. for 1 h, whereupon the reaction mixture was diluted with EtOAc (40 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to give 649 mg (94%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 4.44-4.33 (m, 1 H), 3.75 (t, J=8.5 Hz, 2 H), 3.13-2.99 (m, 2 H), 2.98-2.92 (m, 2 H), 2.91-2.81 (m, 2 H), 2.42 (s, 3 H). m/z (APCI+) for C11H12ClF2N3S 292.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]([NH2:22])=[O:21])=[CH:4][CH:3]=1.CO[C:27](OC)([N:29](C)C)[CH3:28]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]2[O:21][N:29]=[C:27]([CH3:28])[N:22]=2)=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C(N)=O)n2Cc1ccc(F)cc1
Reactant: COC(C)(OC)N(C)C
Product: Cc1noc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)n1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-fluorobenzyl)-5-methanesulfonylindole-2-carboxamide (63 mg) and dimethylacetamide dimethylacetal (1 ml) was stirred at 110° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. A mixture of the resulting residue, hydroxylamine hydrochloride (25 mg), a 2N aqueous sodium hydroxide solution (0.18 ml), 1,4-dioxane (0.4 ml) and acetic acid (0.4 ml) was stirred at 90° C. for 2 hours. Water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 50 mg of the desired product as a white crystal.
Reaction SMILES: [S:1](Cl)([OH:4])(=O)=[O:2].[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][CH:10]=1.[NH3:19]>>[F:18][C:7]([F:6])([F:17])[O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:10]=1[S:1]([NH2:19])(=[O:4])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)Oc1ccc(Cl)c(Cl)c1
Reactant: N
Product: NS(=O)(=O)c1cc(Cl)c(Cl)cc1OC(F)(F)F
Reaction time: 1 h

Procedure:
At 20° C., 57 g (0.173 mol) of 2-trifluoromethoxy4,5-dichloro-benzene sulphochloride are metered to 200 ml of a 25% strength ammonia solution. After stirring of the mixture has continued for 1 hour, the solid is filtered off with suction and subsequently washed with water and dried. Yield 44 g (=83% of theory); melting point 181 to 185° C.
Reaction SMILES: [CH3:1][C@@:2]1([OH:15])[C:6]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C@@H:5]([CH3:13])[CH2:4][C@@H:3]1[OH:14].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[OH:15][C@:2]1([CH3:1])[C:6]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C@@H:5]([CH3:13])[CH2:4][C:3]1=[O:14]
Reactant: C[C@H]1C[C@H](O)[C@](C)(O)C12CCCCCC2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@H]1CC(=O)[C@](C)(O)C12CCCCCC2

Procedure:
As described in Example 1, (1R*,2R*,4S*)-/(1R*,2S*,4S*)-1,4-dimethylspiro[4.6]-undecane-1,2-diol (570 mg, 2.69 mmol) was oxidized with pyridinium chlorochromate (630 mg, 2.95 mmol) on Celite® (630 mg) in CH2Cl2 (10+12 mL) at room temp. for 12 h. Standard work-up by vacuum filtration over a pad of Celite® furnished after purification by silica-gel FC (pentane/Et2O, 9:1, Rf=0.10) (1R*,4S*)-1-hydroxy-1,4-dimethylspiro[4.6]undecan-2-one (21 mg, 4%).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:22])=[C:4]([CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[N:31]1([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][C:10]3[C:11]([CH3:12])=[C:2]([F:1])[C:3]([OH:22])=[C:4]([CH:9]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:26][CH:27]=2)[CH:35]=[CH:34][CH:33]=[N:32]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(F)c1O
Reactant: ClCc1ccc(-n2cccn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(F)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (2.52 g) was added to a mixture of methyl 3-fluoro-2-hydroxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (13.5 g), 1-(4-(chloromethyl)phenyl)-1H-pyrazole (8.39 g), sodium carbonate (9.23 g), DME (195 mL) and water (65.0 mL) under argon atmosphere, and the mixture was stirred overnight at 80° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with a mixed solvent of diisopropyl ether-ethyl acetate to give a crude product. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol). The obtained crude products are combined, and washed with diisopropyl ether-ethyl acetate to give the title compound (12.4 g).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:6]=[N:7]2.[NH2:16][CH2:17][C:18]([NH:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)=[O:19].C(N(CC)CC)C>COCCOCCOC.O>[F:13][C:12]([F:15])([F:14])[C:5]1[CH:6]=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([NH:16][CH2:17][C:18]([NH:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)=[O:19])[N:11]=[CH:10][CH:9]=2
Reactant: FC(F)(F)c1cnc2ccnc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2nccc3ncc(C(F)(F)F)cc23)C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Into a 10 mL round-bottom flask, was placed a solution of 5-chloro-3-(trifluoromethyl)-1,6-naphthyridine (as prepared in the previous step, 23.3 mg, 0.10 mmol, 1.00 equiv) in diglyme (3 mL), tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (prepared as described in Example 1, Step E) (27 mg, 0.12 mmol, 1.20 equiv) and triethylamine (30 mg, 0.30 mmol, 3.00 equiv). The reaction mixture was stirred overnight at 120° C. The resulting mixture was diluted with 20 mL of H2O. The resulting solution was extracted with 3×20 mL of dichloromethane. The combined organic layers dried (Na2SO4) and concentrated under vacuum. The title compound was obtained as a gray solid.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@H:7]2[CH2:12][O:11][C@@H:10]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:9][CH2:8]2)=[CH:4][CH:3]=1.[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:22]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C@H:7]3[CH2:8][O:9][C@@H:10]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:11][CH2:12]3)=[CH:20][CH:21]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(=O)NCCC[C@H]1OC[C@@H](Oc2ccc(O)cc2)CO1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)NCCC[C@H]1OC[C@@H](Oc2ccc(OC3CCCC3)cc2)CO1
Reaction time: 8 h

Procedure:
cis-N-{3-[5-(4-Hydroxyphenoxy)-[1,3]dioxan-2-yl]propyl}acetamide (18.6 mg, 0.063 mmol), cyclopentyl bromide (11.3 mg, 0.076 mmol) and cesium carbonate (24.6 mg, 0.076 mmol) were stirred in 3 ml of DMF at room temperature for 3 h. Addition of 11 mg of cyclopentyl bromide and 20 mg of cesium carbonate on each of two occasions was followed by stirring for a total of 8 h and concentrating, and the residue was taken up in ethyl acetate and water. The organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 8.5 mg (37%), M+H+: 364.22.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:12][C:13]1[O:17][C:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:15][C:14]=1[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][C:13]2[O:17][C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=3)=[N:15][C:14]=2[CH3:30])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1CCl
Reactant: N#Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1COc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 2.63 g 2-chloro-4-hydroxy-benzonitrile in 25 ml dimethylformamide were added 4.0 g 5-chloromethyl-4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazole and 8.58 g cesium carbonate. The mixture was stirred at room temperature overnight. Then 150 ml of ethyl acetate were added, the mixture washed with 40 ml water and brine and then dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by RP-HPLC to obtain 3.0 g 2-chloro-4-{4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazol-5-ylmethoxy}-benzonitrile.
Reaction SMILES: [CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C:3]1[S:43][C:6]2[N:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:8](=[O:23])[N:9]([CH2:12][CH:13]([OH:14])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1cc2c(=O)n(CC(O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To a mixture of 6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.2 g) and methanol (15 mL) was added sodium borohydride (0.025 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was extracted with chloroform and saturated aqueous ammonium chloride solution. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.12 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC>C1COCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:6]1[CH:7]=[C:2]([NH2:1])[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: C1CCOC1
Product: Nc1cc(-c2ccccn2)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 168 h

Procedure:
The title compound Is synthesized via Stille coupling analogously to the procedure of Zhang et al., Synthetic Commun. 31 (8), 1129-1139 (2001) 3-amino-5-bromo-benzotrifluoride (600 mg, 2.44 mmol), 2-tributylstannyl-pyridine (1.0 g, 2.69 mmol), and tetrakistriphenylphosphin palladium (282 mg, 0.245 mmol) dissolved in THF (10 mL) is stirred under Ar at 90° C. for 7 d. After concentrating under reduced pressure, the reaction mixture is flash chromatographed (silica gel, 2.6×46 cm, AcOEt/hexane: 1:2→2:3) to give compound of Stage 146.1 as a yellow oil: M+H=239.1; 1H-NMR (400 MHz, DMSO-d6): 8.64 (d, 5.0 Hz, 1H), 7.82 (m, 2H), 7.54/7.45 (s/s, 1H/1H), 7.36 (m, 1H9, 6.90 (s, 1H), 5.73 (s/broad, 2H); HPLC: 3.49 min (System 1); Rf (hexane/AcOEt=2:1): 1.5.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:15]=1[C:16](Cl)=[O:17]>>[CH3:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:15]=1[C:16]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:17]
Reactant: CN1CCc2c(N)cccc2C1
Reactant: Cc1cccc(C)c1C(=O)Cl
Product: Cc1cccc(C)c1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2,6-dimethylbenzoyl chloride according to the procedure of Example 19 to yield 5-(2,6-dimethylbenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 199.5°-201° C. after purification from ethanol.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=1.[Br:30][C:31]1[N:36]=[C:35]([CH:37](O)[CH2:38][O:39][CH2:40][CH3:41])[CH:34]=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:30][C:31]1[N:36]=[C:35]([CH:37]([O:15][C:16]2[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=2)[CH2:38][O:39][CH2:40][CH3:41])[CH:34]=[CH:33][CH:32]=1
Reactant: CCOCC(O)c1cccc(Br)n1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
A solution of diisopropylazodicarboxylate (0.96 mL, 4.89 mmol) in dry THF (35 mL) was added drop-wise, under nitrogen, over 2 h (using a syringe pump) to a solution of ethyl (4-hydroxy-2-methylphenoxy)acetate (735 mg, 3.50 mmol), 1-(6-bromo-2-pyridinyl)-2-(ethyloxy)ethanol (860 mg, 3.49 mmol) and triphenylphosphine (1.28 g, 4.88 mmol) in dry THF (35 mL) at 0° C. The resulting mixture was stirred under nitrogen and gradually allowed to warm to room temperature over 21 h. The solvent was then removed in vacuo and the residue purified by SPE (silica, 2×50 g cartridge), eluting with cyclohexane:EtOAc (gradient 20:1 to 1:1) to afford the title compound as an oil (966 mg).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C:12]([C:14]1[CH:40]=[CH:39][C:17]([O:18][CH2:19][CH:20]([OH:38])[CH2:21][N:22]2[CH2:29][CH:28]3[CH2:30][CH:24]([CH2:25][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]3)[CH2:23]2)=[CH:16][CH:15]=1)#[N:13]>C(Cl)Cl>[C:34]([O:33][C:31]([N:26]1[CH2:25][CH:24]2[CH2:30][CH:28]([CH2:29][N+:22]([CH2:21][CH:20]([OH:38])[CH2:19][O:18][C:17]3[CH:16]=[CH:15][C:14]([C:12]#[N:13])=[CH:40][CH:39]=3)([O-:9])[CH2:23]2)[CH2:27]1)=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3)C2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CC(C1)C[N+]([O-])(CC(O)COc1ccc(C#N)cc1)C2
Reaction time: 1 h
Yield: 98 %

Procedure:
mCPBA (300 mg; 70%; 1.22 mmol) was added to a stirred solution of tert-butyl 7-[3-(4-cyanophenoxy)-2-hydroxypropyl]-3,7-diazabicyclo-[3.3.1]nonane-3-carboxylate (490 mg; 1.22 mmol; see Example 2 above) in DCM (10 mL) at 0° C. The reaction mixture was stirred for 1 h and then washed with NaHCO3 (aq.). The organic layer separated, dried, concentrated and subjected to column chromatography (DCM:MeOH; 19:1) to give the title compound in a 98% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]1)(=[O:10])=[O:9].[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:19]2[CH:20]=[CH:21][C:22]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([N:11]3[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]3)(=[O:10])=[O:9])=[CH:23][C:18]=2[F:17])=[CH:34][N:35]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: N#CC1CN(S(=O)(=O)c2ccccc2Br)C1
Product: N#CC1CN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)C1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 1-((2-bromophenyl)sulfonyl)azetidine-3-carbonitrile and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C20H16FN5O2S, 409.10; m/z found, 409.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 2H), 8.08-8.00 (d, J=8.0, 1H), 7.83-7.75 (m, 1H), 7.71-7.65 (m, 1H), 7.65-7.58 (m, 1H), 7.51-7.43 (d, J=7.5, 1H), 7.38-7.31 (d, J=11.7, 1H), 7.31-7.26 (m, 1H), 6.89 (s, 2H), 3.96-3.87 (m, 2H), 3.68-3.59 (m, 3H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15]([C:25]#[N:26])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:14][CH2:13]1)=O)(C)(C)C.Cl.CCOC(C)=O>C(OCC)(=O)C>[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][C:15]([C:25]#[N:26])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH2:16][CH2:17]1
Reactant: Cc1ccccc1C1(C#N)CCN(CCCNC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1C1(C#N)CCN(CCCN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 25 (7.90 g, 22.0 mmol) in ethyl acetate (200 mL) was cooled to 0° C. and treated with sat'd HCl/EtOAc solution (200 mL). The mixture was stirred at room temperature (1 h). The solvent was partially removed in vacuo and the mixture diluted with ethyl acetate and sodium carbonate solution. The aqueous layer was extracted with two additional portions of ethyl acetate and three portions of dichloromethane. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound (26). The crude product was used directly.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][C:24]1[O:32][C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]3[CH2:23][C:24]3[O:32][C:31]4[C:26](=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[O:16])=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Reactant: c1cnc2cc(CC3CCCCN3)oc2c1
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCCC2Cc2cc3ncccc3o2)n1

Procedure:
The title compound was prepared using the method of Example 4, from 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (110 mg, 0.5 mmol) and (RS)-2-Piperidin-2-ylmethyl-furo[3,2-b]pyridine, D47 (108 mg, 0.5 mmol), as a colourless solid (130 mg, 62%).
Reaction SMILES: C([O-])C=C.[Na+].C([O:9][C:10]([C@H:12]1[C@H:17]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:16]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C@@H:15]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@H:14]([O:42][C:43]2[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][C:44]=2[CH:52]2[O:56][CH2:55][CH2:54][O:53]2)[O:13]1)=[O:11])C=C>C(O)C=C>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][C@@H:17]1[C@H:16]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C@@H:15]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])[C@H:14]([O:42][C:43]2[CH:48]=[CH:47][C:46]([N+:49]([O-:51])=[O:50])=[CH:45][C:44]=2[CH:52]2[O:56][CH2:55][CH2:54][O:53]2)[O:13][C@@H:12]1[C:10]([OH:11])=[O:9])([CH3:23])([CH3:24])[CH3:25]
Reactant: C=CCOC(=O)[C@@H]1O[C@@H](Oc2ccc([N+](=O)[O-])cc2C2OCCO2)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1O[Si](C)(C)C(C)(C)C
Agent: C=CC[O-]
Agent: [Na+]
Solvent: C=CCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C(=O)O)O[C@@H](Oc2ccc([N+](=O)[O-])cc2C2OCCO2)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 100.4 %

Procedure:
The solution of 5.64 g (7.58 mmol) of the compound, presented according to Example LE3d, in 150 ml of allyl alcohol is mixed with 9.1 ml of a 1 M solution of sodium allyl alcoholate in allyl alcohol, and it is stirred for 2.5 hours at 50° C. It is concentrated by evaporation, mixed with water, extracted several times with dichloromethane, the combined organic extracts are washed with saturated sodium chloride solution and dried on magnesium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel, and 1.78 g (2.44 mmol, 32%) of the title compound as well as 1.87 g (2.43 mmol, 32%) of (2R,3S,4S,5R,6S)-3,4,5-tris-(tert-butyl-dimethyl-silanyloxy)-6-(2-[1,3]dioxolan-2-yl-4-nitro-phenoxy)-tetrahydro-pyran-2-carboxylic acid allyl ester are isolated.
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1.[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)=[O:28]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of pyridine (18 μl, 0.22 mmol) and 4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine (Example 51, 50 mg, 022 mmol) in CH2Cl2 (4 ml) was treated with 3,3-dimethylbutanoyl chloride (58 mg, 0.43 mmol). The reaction was stirred at rt for 18 h then quenched with saturated aqueous NaHCO3 (1 ml). The organic phase was separated, evaporated and the residue purified by flash chromatography (IH-EtOAc, 1:1 to 0:1) to afford the title compound: RT=3.1 min, m/z (ES+)=329.3 [M+H]+.