Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[CH:11]=[N:10]1.P(Br)(Br)[Br:20]>C(Cl)Cl.O>[Br:20][CH2:14][C:13]1[N:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[N:10]=[CH:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CO
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
To a solution of (1-(2,6-dichlorophenyl)-4-isopropyl-1H-pyrazol-5-yl)methanol (4.0 g, 0.014 mol) in CH2Cl2 (50 ml) is added phosphorus tribromide (5.69 g, 0.021 mol) at 0° C. Stir the mixture for 3 h at room temperature. Dilute with water and extract with ethyl acetate. Concentrate under reduced pressure, to give crude product, which is purified by column chromatography over silica gel eluting with 7:3 hexane/ethyl acetate to give 0.50 g (10%) of the title compound. ES/MS m/e (81Br) 348.93 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]([CH3:29])=[CH2:28])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](OCCCC)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].O.[NH2:31][NH2:32]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:26][C:27]([CH3:29])=[CH2:28])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([NH:31][NH2:32])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: NN
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)OCCCC)nn1
Solvent: CCO
Solvent: O
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)NN)nn1

Procedure:
Butyl 6-[N-(5-bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carboxylate (reference example 4) (4.3 g, 9.3 mmol) was dissolved in ethanol (170ml) with hydrazine hydrate (17 ml, 330 mmol) and heated at reflux for 16 hours. The solvent was removed in vacuo, and the residue treated with ethyl acetate/water (200 ml of each). The organic phase separated off and the aqueous phase reextracted with ethyl acetate (2×200 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the title compound as an oil which crystallised on standing (3.66 g, 94%).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].[CH3:20][CH:21]([N-]C(C)C)[CH3:22].C(Br)C=C.CCCCCC>C1COCC1>[CH2:22]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1)[CH:21]=[CH2:20]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.8 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (5 g, 19.37 mmol) in THF (50 mL) was cooled to −78° C. followed by drop wise addition of LDA (1.80 M in THF, 21.67 mL, 38.74 mmol) solution and was stirred at the same temperature for 45 min followed by addition of allyl bromide (5 mL, 58.14 mmol) at −78° C. The temperature of the reaction was slowly raised to rt and left to stir for 5-6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 1% EtOAc:hexane to obtain the product as an orange viscous liquid (5 g, 87% yield). MS: 298.19 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:11]=[C:12]([NH2:14])[N:13]=2)[CH:5]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[C:3]3[N:4]([N:11]=[C:12]([NH2:14])[N:13]=3)[CH:5]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[CH:7]=2)=[CH:18][CH:17]=1
Reactant: Nc1nc2c(Br)cc(C3CC3)cn2n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc2c(-c3ccc(Cl)cc3)cc(C3CC3)cn2n1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of 8-bromo-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (300 mg, 1.29 mmol) and 4-chlorophenyl boronic acid (463 mg, 2.96 mmol) in dioxane (15 mL) was added an aqueous solution of Na2CO3 (2 M, 2 mL) and degassed with argon for 5 minutes. PdCl2 (dppf)2.CH2Cl2 (30.34 mg, 0.04 mmol) was added and stirred at 80° C. for 90 minutes. The reaction mixture was cooled to room temperature and water (20 mL) was added. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as an off white solid (252 mg, 75%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=O)[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].Cl.Cl.[NH2:16][O:17][CH2:18][CH2:19][NH2:20].C(=O)(O)[O-].[Na+]>C(O)C.O>[NH2:20][CH2:19][CH2:18][O:17][N:16]=[C:9]([C:7]1[N:8]=[C:4]([NH:3][CH:1]=[O:2])[S:5][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: NCCON
Reactant: O=CNc1nc(C(=O)C(=O)O)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
To a solution of 2-(2-formamidothiazol-4-yl)glyoxylic acid (5.5 g.) in ethanol (100 ml.) was added a solution of 2-(aminooxy)ethylamine.dihydrochloride (4.1 g.) in water (50 ml). The resulting mixture was adjusted to pH 4 with an aqueous solution of sodium bicarbonate and stirred for 3 hours at room temperature. The reaction mixture was evaporated to a volume of 100 ml. and cooled. The resulting precipitates were collected by filtration, washed successively with cold-water and ethanol to give the title compound (6.5 g.), mp 213° to 214° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:36][CH:35]=[CH2:34])=[CH:11][C:10]=1[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: O=C(O)c1ccc(CCCc2cc(O)ccc2OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(OCc2ccccc2)c(CCCc2ccc(C(=O)O)cc2)c1
Reaction time: 18 h

Procedure:
To a mixture of 4-[3-(2-benzyloxy-5-hydroxyphenyl)propyl]- benzoic acid (150 mg) (prepared as described in Example 4) and potassium carbonate (125 mg) in DMF (5 ml) was added allyl bromide (0.076 ml). The mixture was stirred for 18 hours, then potassium carbonate (125 mg) and allyl bromide (0.076 ml) were added and the mixture stirred for a further 18 hours. The mixture was poured into water (50 ml) and extracted with ethyl acetate (2×20 ml). The combined organics solutions were washed with brine (25 ml) and sodium bicarbonate (25 ml), dried (magnesium sulphate) filtered and evaporated. There was thus obtained allyl 4-[3-(2-benzyloxy-5-(allyloxy)phenyl)propyl]benzoate (150 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CC(C)([O-])C.[K+]>O.CN1CCCC1=O>[CH3:18][C:17]1[C:12]([NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1cccnc1N
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccnc1Nc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 36.9 %

Procedure:
0.3 g of 4-fluoronitrobenzene, 0.46 g of 2-amino-3-methylpyridine, and 0.353 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 1 hour and 0.286 g of potassium tert-butoxide was then added. Heating was then continued for 6 hours and, after cooling to room temperature, the reaction medium was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.18 g of 3-methyl-N-(4-nitrophenyl)pyrid-2-amine (7) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](OC)[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:19]([OH:21])C>>[CH3:19][O:21][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:7]=1
Reactant: COc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C1CCNCC1
Reactant: CCO
Product: COc1ccc([N+](=O)[O-])c(N2CCCCC2)n1
Temperature: 0 °C

Procedure:
4 g (0.02 mol) of 6-chloro-2-methoxy-3-nitropyridine, 60 ml of ethanol and 4.2 ml of piperidine are charged to a fully equipped round-bottomed flask. The mixture is brought to reflux for two hours with stirring and then the mixture is poured onto an ice/water mixture with stirring. The precipitate formed is filtered off and dried. 2 g of yellow powder are obtained, Yd=42.5%.
Reaction SMILES: C1O[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[CH:7](C3CCCCC=3)[CH2:6]2)OC1C.C(OCC)(=O)C.[CH2:32]([OH:34])[CH3:33].C(O)=O.[C:38]1(C)[CH:43]=CC=[CH:40][CH:39]=1>[Ni].O>[F:17][C:15]1[CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][CH:5]([CH:33]3[CH2:40][CH2:39][CH2:38][CH2:43][C:32]3=[O:34])[CH2:6][CH2:7]2)[CH:12]=[C:13]([F:18])[CH:14]=1
Reactant: CCO
Reactant: CC1COC2(CCC(c3cc(F)cc(F)c3)C(C3=CCCCC3)C2)O1
Reactant: Cc1ccccc1
Agent: [Ni]
Solvent: O=CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCCCC1C1CCC(c2cc(F)cc(F)c2)CC1
Yield: 59.3 %

Procedure:
The above 4-(3,5-difluorophenyl)-3-cyclohexenyl-1-cyclohexanone propyleneketal (114 g, 327 mmol) was hydrogenated in a mixed solvent of ethyl acetate with ethanol in the presence of Raney Ni catalyst (44.8 g), followed by filtering off the catalyst, distilling off the solvent under reduced pressure, adding to the residue, formic acid (50.0 g, 1.09 mol) and toluene (300 ml), refluxing the mixture for 4 hours, adding water to the reaction solution, washing the organic layer successively with a saturated aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off toluene under reduced pressure, and purifying the residue according to column chromatography treatment using toluene as a developing solvent, on silica gel, to obtain 4-(3,5-difluorophenyl)cyclohexyl-1-cyclohexanone (56.8 g, 194 mmol). Yield: 59.3%.
Reaction SMILES: ClCC([NH:5][C:6]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=2)[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[O:9][CH2:8][CH2:7]1)=O.NC(N)=S>CCO.CC(O)=O.CCOC(C)=O>[F:26][C:23]([F:24])([F:25])[O:22][C:19]1[CH:20]=[CH:21][C:16]([C:6]2([NH2:5])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[O:9][CH2:8][CH2:7]2)=[CH:17][CH:18]=1
Reactant: O=C(CCl)NC1(c2ccc(OC(F)(F)F)cc2)CCOc2cccnc21
Agent: NC(N)=S
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC1(c2ccc(OC(F)(F)F)cc2)CCOc2cccnc21
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 2-chloro-N-(4-(4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)acetamide (1.5 g, 3.8 mmol) in EtOH (5 times) and AcOH (cat.), was added thiourea (0.3 g, 4.2 mmol). The reaction was stirred at 60° C. for 12 h. The progress of reaction was monitored by TLC (50% EtOAc in petroleum ether). The reaction was diluted with EtOAc (10 mL) and quenched slowly with saturated NaHCO3 (25 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, and concentrated to give the product as a residue. Purification by column chromatography (60-120 mesh silica, 0-50% EtOAc/hexanes) gives the title compound as a brown oil. MS (ESI pos. ion) m/z: 294.1 (M-NH2). 1H NMR (300 MHz, CDCl3): δ 8.2 (d, J=4.0 Hz, 1H), 7.3 (m, 2H), 7.1-7.2 (m, 4H), 4.3 (m, 1H), 4.0 (m, 1H), 2.35-2.45 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>CN(C=O)C.O>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1
Reactant: Clc1ccc2ccccc2n1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: OC1CCN(c2ccc3ccccc3n2)CC1
Temperature: 100 °C
Yield: 58.8 %

Procedure:
Triethylamine (2.9 g, 29.6 mmol), 2-chloro-quinoline (purchased from Alfa Aesar™) (2.4 g, 14.8 mmol) and piperidin-4-ol (1.5 g, 14.8 mmol) were dissolved in DMF (20 mL). The resulting mixture was heated to 100° C. overnight. The mixture was then diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were combined and washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 70% EtOAc in petroleum ether) to give 1-(quinolin-2-yl)piperidin-4-ol (2.0 g, 8.7 mmol, 60% yield) as white solid. ESI-MS (M+1): 229 calc. for C14H16N2O 228.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16]N=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](OC(N1CCN(C2C=CC(Br)=CN=2)CC1)=O)(C)(C)C.FC1C=CC(B(O)O)=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:27]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1
Agent: OB(O)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1
Yield: 99 %

Procedure:
Prepared according to the method for the preparation of 4-[5-(4-fluorophenyl)-pyrimidin-2-yl]piperazine-1-carboxylic acid tert-butyl ester, from 4-(5-bromo-pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (0.151 g) and 4-fluorophenylboronic acid (0.068 g), to give the title compound as a white solid (0.155 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](C(O)C)[O:4][N:3]=1.S(=O)(=O)(O)O.[OH2:15].[Cl-].[Na+].C[C:19]([CH3:21])=[O:20]>>[CH3:1][C:2]1[CH:6]=[C:5]([O:20][C:19](=[O:15])[CH3:21])[O:4][N:3]=1
Reactant: Cc1cc(C(C)O)on1
Reactant: O
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CC(=O)Oc1cc(C)no1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 3-methyl-5-(1-hydroxyethyl)-isoxazole (47.6 g, 367 mM) in acetone (2 L) at 0° C., was added a solution of chromic anhydride (93.3 g, 933 mM), 6N aqueous sulfuric acid (186.15 mL, 1.1M) and water (186 mL) over two hours. After the reaction solution was allowed to warm to room temperature, saturated aqueous sodium chloride was added. The aqueous layer was extracted with dichloromethane (3×400 mL). The combined organic extracts were washed with saturated aqueous sodium sulfite (2×300 mL) and saturated aqueous sodium chloride (2×300 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give 3-methyl-5-acetoxy-isoxazole as a yellow powder (27.8 g, 60%) that was used without further purification. 1H NMR (CDCl3, 100 MHz): δ 7.55 (s, 1H), 2.65 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:17][C:11]=3[CH:10]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:32][CH2:33][CH2:34][N:35]1[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:36]1=[O:43].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:17][C:11]=3[CH:10]=2)=[N:4][C:5]([NH:32][CH2:33][CH2:34][N:35]2[C:39]([CH3:40])([CH3:41])[C:38](=[O:42])[NH:37][C:36]2=[O:43])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc2sc(-c3nc(Cl)ncc3Br)cc2c1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc2sc(-c3nc(NCCN4C(=O)NC(=O)C4(C)C)ncc3Br)cc2c1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
A mixture of (2S)-tert-butyl 2-((2-(5-bromo-2-chloropyrimidin-4-yl)benzo[b]thiophen-5-yloxy)methyl)pyrrolidine-1-carboxylate (524 mg, 1.00 mmol) in toluene (25 mL) was treated with 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione (205 mg, 1.20 mmol) and triethylamine (121 mg, 1.2 mmol) and then heated to reflux in an oil bath for 3 h. The reaction was cooled to room temperature, diluted with ethyl acetate (25 mL) and washed in turn with a saturated aqueous solution of sodium bicarbonate (15 mL), deionized water (15 mL), and a saturated aqueous solution of sodium chloride (15 mL). The organic layer was separated, dried over sodium sulfate (300 mg), filtered through a coarse frit (to remove the sodium sulfate), and condensed in vacuo to give a white solid (450 mg). The crude material was purified by flash chromatography (EtOAc/hexane v/v) to yield the title compound as a white solid (325 mg, 50%). MS (M+H)+ 659/661.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])[CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=3)[C:21]#[N:22])[CH:16]=2)[NH:11][N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C#N)c3)cc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C#N)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
3-[3-(2-Methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzonitrile (22 mg, 0.048 mmol) was dissolved in 1 mL trifluoroacetic acid. The mixture was stirred at room temperature for 1 h and the solvent was evaporated. The crude product was dissolved in 1 mL of methanol and 50 μL of ethylenediamine was added. After 15 min, 1 mL of DMSO was added and the mixture was directly purified by mass-triggered preparative reverse phase HPLC to give 3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzonitrile as a colorless solid (4.6 mg, 30% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.90 (d, J=2.5 Hz, 1H), 8.44 (d, J=2.5 Hz, 1H), 8.28 (t, J=2 Hz, 1H), 8.12 (m, 2H), 7.84 (dt, J1=8 Hz, J2=1 Hz, 1H), 7.67 (t, J=7.5 Hz, 1H), 7.64 (dd, J=7.5 Hz, J2=2 Hz, 1H), 7.46 (m, 1H), 7.21 (d, J=8 Hz, 1H), 7.09 (td, J1=7.5 Hz, J2=1 Hz, 1H), 3.83 (s, 3H); MS: m/z 327 [MH+].
Reaction SMILES: C(OC([N:8]([CH3:18])[C@@H:9]([CH2:13][C:14](C)(C)C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[N:25][CH:26]=1.[F:38]C(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[F:38][C@H:14]1[CH2:18][NH:8][C@H:9]([C:10]([NH:35][C@@H:32]2[C@@H:30]3[C@@H:29]([CH2:28][N:27]([C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:26][N:25]=4)[CH2:31]3)[CH2:34][CH2:33]2)=[O:12])[CH2:13]1
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: O=C(N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21)[C@@H]1C[C@@H](F)CN1

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-trans-4-fluoro-L-proline for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 262 Step B for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.65-8.59 (m, 1H), 8.33 (d, J=7.5 Hz, 1H), 7.67 (dd, J=8.9, 2.5 Hz, 1H), 6.36 (d, J=8.9 Hz, 1H), 5.20 (dt, J=54.4, 3.5 Hz, 1H), 4.36-4.23 (m, 2H), 3.75 (d, J=8.4 Hz, 1H), 3.66-3.52 (m, 3H), 3.30 (dt, J=15.2, 7.6 Hz, 2H), 2.91 (dd, J=38.5, 11.2 Hz, 1H), 2.77-2.68 (m, 1H), 2.68-2.52 (m, 2H), 2.25 (dddd, J=39.3, 14.8, 7.9, 4.4 Hz, 1H), 2.11 (ddd, J=19.5, 7.2, 4.9 Hz, 1H), 1.92 (dtd, J=13.0, 8.1, 4.8 Hz, 1H), 1.62 (dq, J=12.7, 8.2 Hz, 1H), 1.39 (dtd, J=13.4, 7.9, 5.7 Hz, 1H); MS (ESI+) m/z 387 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([OH:15])[CH2:6][P:7]([CH3:14])(=[O:13])[O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][CH2:4][C@H:5]([OH:15])[CH2:6][P:7]([CH3:14])(=[O:13])[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: [H][H]
Reactant: CC(C)COP(C)(=O)C[C@@H](O)CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)COP(C)(=O)C[C@@H](O)CN

Procedure:
To a solution of 1.2 g of isobutyl P-[3-azido-2(S)- hydroxy-propyl]-P-methyl-phosphinate in 25 ml of ethanol are added 0.25 g of 5% palladium on charcoal. The resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate evaporated to give isobutyl P-[3-amino-2(S)-hydroxy-propyl]-P-(methyl)-phosphinate as a viscous oil, 31P-NMR spectrum: δ=+55.6 and +54.6 ppm (CDCl3), [α]D25 =+10.9(c=0.50% in ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccccc1
Yield: 94.3 %

Procedure:
A solution of 4-chloro-3-nitro-phenol (2.0 g, 11.5 mmol), 1-bromoethyl-benzene (3.2 g, 17.3 mmol), sodium carbonate (1.80 g, 17.0 mmol) in acetone (20 ml) was heated at reflux for 18 hours. The reaction mixture was cooled, the solids filtered off and the filtrate concentrated to a thick syrup under vacuum. The residue was dissolved in ether (80 ml) and washed with water (20 ml) and 30% KOH solution (2×20 ml) and the solvent is concentrated under vacuum leaving an oily residue as the title compound (3.01 g, 94%).