Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH2:19][O:18]1>CS(C)=O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:17]1([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH2:19][CH2:4][O:18]1
Reactant: C[S+](C)(C)=O
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1ccc(C2(Cn3cncn3)CCO2)c(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
101 mg (4.2 mmole) of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to 10 ml of dimethyl sulfoxide, and the resulting mixture was stirred at 80° C. for 30 minutes. At the end of this time, the mixture was cooled, 928 mg (4.2 mmole) of trimethylsulfoxonium iodide were added thereto and the reaction temperature was allowed to rise to room temperature. The mixture was then stirred for 30 minutes, after which 501 mg (2.11 mmole) of 2-(2,4-difluorophenyl)-2-[(1H-1,2,4-triazol-1-yl)methyl]-oxirane was added, and the mixture was stirred at 50° C. for a further 16 hours. At the end of this time, the reaction mixture was cooled, poured into 50 ml of ice-water and extracted with 100 ml of ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, eluted with a 2:3 by volume mixture of hexane and ethyl acetate, to afford 238 mg (yield 45%.) of the title compound as an oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:3]=1.C(N(CC)CC)C.[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30]>CN(C=O)C.O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:33][O:32][C:28](=[O:31])[CH:29]=[CH:30][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:3]=1
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc([N+](=O)[O-])ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C=Cc1nn(C(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])cc12
Temperature: 50 °C
Yield: 36.6 %

Procedure:
A solution of tert-butyl 3-iodo-5-nitro-1H-indazole-1-carboxylate (Intermediate 44, 4.6 g; 11.8 mmol) in DMF (76 ml) and water (12 ml) was treated with triethylamine (12 ml; 86 mmol), methyl acrylate (10.4 ml; 115 mmol) and tetrabutyl ammonium iodide (8.6 g; 23 mmol). The mixture was degassed and then dichlorobis(triphenylphosphine)palladium (II), (1.68 g; 2.4 mmol) was added. The mixture was heated to 50° C. for 18 hours and the volatile solvent removed in vacuo. The mixture was poured into water (600 ml) and extracted with EtOAc. The combined organic extracts were washed with water, dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 3-(3-methoxy-3-oxoprop-1-enyl)-5-nitro-1H-indazole-1-carboxylate as a light brown solid (1.5 g, 37%). A solution of this residue (200 mg; 0.58 mmol) in methanol (100 ml) was treated with palladium (100mg, 5% on C). The mixture was stirred under hydrogen for 18 hours, filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][O:6]1)([O-:3])=[O:2].ClC1C=C(Cl)C=C(Cl)C=1[O:19][C:20](=O)[CH:21]([CH3:34])[C:22](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:23].C(OC(=O)C)C>C1(C)C(C)=CC=CC=1.CCCCCC>[OH:23][C:22]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[O:6][CH2:7][CH2:8][N:9]2[C:20](=[O:19])[C:21]=1[CH3:34]
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: O=[N+]([O-])C=C1NCCO1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: Cc1c(O)c([N+](=O)[O-])c2n(c1=O)CCO2
Temperature: 125 °C
Yield: 30.7 %

Procedure:
2-Nitromethylene-oxazolidine (3 g, 23.0 mmol) was added portion wise to a stirred solution of 2-methyl-malonic acid bis-(2,4,6-trichloro-phenyl) ester (12 g, 25.15 mmol) in Xylene (50 mL) under nitrogen atmosphere over a period of 1 hour at 125° C. The resulting mixture was heated to 125° C. for 5 hours. The reaction mixture was monitored by TLC (50% ethylacetate in hexane). The reaction mixture was concentrated and the concentrate was purified by column chromatography on silica gel (60% ethylacetate in hexane) to afford 1.5 g of the product (30% yield).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:36]=[CH:35][N:14]3[C:15](=[O:34])[C:16](/[CH:25]=[CH:26]/[C:27]([O:29]C(C)(C)C)=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]>C(O)=O>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:36]=[CH:35][N:14]3[C:15](=[O:34])[C:16](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCOCC4)nc3c2)n1
Solvent: O=CO
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)n1
Yield: 86.4 %

Procedure:
The tert-butyl (E)-3-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (39 mg) obtained in (D) was stirred in formic acid (1 ml) for 4.5 hours, and the solvent was evaporated under reduced pressure to obtain the title compound (30 mg).
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1.[Si:9](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>C(Cl)Cl>[Si:9]([O:2][CH2:3][C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1c[nH]cn1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OCc1c[nH]cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
4-Hydroxymethylimidazole hydrochloride ACROS (5 g, 37.1 mmol) was suspended in CH2Cl2 (100 ml) and TEA (12.87 ml, 92.8 mmol) was added. The solution was cooled at 0° C. and tert-butyldiphenylsilylchloride (15.3 ml, 55.7 mmol) was added. The reaction mixture was stirred for 30 min at 0° C. and at room temperature for 3.5 h. Water was added, the organic extract was washed with water and brine, then died over MgSO4. The solvent was removed under reduced pressure and the resulting oil was crystallized from diisopropylether to afford a white solid (8.17 g, m.p.=135° C.).
Reaction SMILES: [C@H:1]1([O:12][C@H:13]2[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C@H:22]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@@H:23]3[OH:24])[O:16][C@H:15]([O:33][CH2:34][CH2:35][NH:36][C:37](=[O:52])[CH2:38][CH2:39][CH2:40][CH2:41][C:42]([O:44]CC3C=CC=CC=3)=[O:43])[C@H:14]2[OH:53])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]>O.[Pd]>[C@H:1]1([O:12][C@H:13]2[C@H:18]([OH:19])[C@@H:17]([CH2:20][O:21][C@H:22]3[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@@H:23]3[OH:24])[O:16][C@H:15]([O:33][CH2:34][CH2:35][NH:36][C:37](=[O:52])[CH2:38][CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[C@H:14]2[OH:53])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: O=C(CCCCC(=O)OCc1ccccc1)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Agent: [Pd]
Solvent: O
Product: O=C(O)CCCCC(=O)NCCO[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of benzyl 6-({2-[(α-D-mannopyranosyl-(1→3)-[α-D-mannopyranosyl-(1→6)]-α-D-mannopyranosyl)oxy]ethyl}amino)-6-oxohexanoate (1.15 g, 1.502 mmol) and Pd/C (80 mg, 0.075 mmol) in water (10 mL) was allowed to stir under a balloon of H2 at room temperature for 16 hr. The catalyst was filtered off and washed with H2O (3×10 mL). The filtrate was concentrated to give the title compound. UPLC Method B: calculated for C26H45NO19 675.26, observed m/e: 676.21 [M+1]; Rt=3.50 min.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](F)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[F:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17][NH2:18].CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:18][CH2:17][CH2:16][CH2:15][C:14]([F:20])([F:19])[F:13])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: NCCCC(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: FC(F)(F)CCCNc1ccc2ncc(Br)n2n1
Yield: 93.7 %

Procedure:
A stirred solution of 3-bromo-6-fluoro-imidazo[1,2-b]pyridazine (1.7 g, 7.6 mmol), 4,4,4-trifluoro-butylamine hydrochloride [84153-82-2] (1.3 g, 7.6 mmol), and Hunig's base [7087-68-5] (4.0 mL, 23.0 mmol) in 2-propanol (40 mL) was heated to 65° C., under N2 blanket for 3d, cooled, and partitioned between brine (pH adjusted to 10 with 3N aqueous sodium hydroxide) and ethyl acetate. The phase separated extract was dried (MgSO4) and evaporated to provide 2.3 g of yellow solid. LRMS (ESI) m/z 323.1/325.1 [(M+H)]+, calc'd for C10H10BrF3N4: 323.12.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[C:3]#[N:4].[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>C1COCC1.C(OCCCC)CCC.CO>[CH3:1][C:2]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:5])[CH:3]([NH2:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Li]c1ccccc1
Reactant: CC(C)(C#N)N1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCOCCCC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C(N)c1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-2-(1-pyrrolidinyl)propanenitrile D4 (40 g; 289.85 mmol) in dry THF (0.8 L) under nitrogen, cooled at −78° C., was added dropwise a solution of phenyl lithium in dibutyl ether over 40 minutes (305.1 mL of a 1.9M solution; 579.70 mmol). After 2 h the reaction was allowed to reach room temperature and then stirred overnight at this temperature. The mixture was quenched at 0° C. with a saturated solution of NaHCO3 (0.8 L) and stirred for 15 minutes and diluted with water (ca. 0.6 L). The phases were separated and the aqueous back extracted with diethylether (2×1 L). The collected organics were dried over Na2SO4 and evaporated in vacuo to get 90 g of crude material as a yellow oil that was dissolved in methanol (1 L) at 0° C. and treated portionwise with sodium borohydride (21.93 g; 579.70 mmol). After 1 hour at 0° C. and then overnight at room temperature the mixture was cooled and quenched with water (ca. 0.5 L). Methanol was evaporated in vacuo and the aqueous phase, diluted with water (200 mL), was extracted with DCM (3×800 mL). The collected organics were dried over Na2SO4 and evaporated in vacuo to get the title product (51 g) as a yellow solid, used in step 2 without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8][C:7]=2[N:20]=1.[CH:22](=O)[CH3:23]>CCO.[Pd]>[CH2:22]([NH:21][C:4]1[C:3]([O:2][CH3:1])=[N:20][C:7]2[CH2:8][CH2:9][N:10]([C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:11][CH:12]([CH3:13])[C:6]=2[CH:5]=1)[CH3:23]
Reactant: COc1nc2c(cc1N)C(C)CN(C(=O)C(F)(F)F)CC2
Reactant: CC=O
Agent: [Pd]
Solvent: CCO
Product: CCNc1cc2c(nc1OC)CCN(C(=O)C(F)(F)F)CC2C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
A mixture of 2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H -pyrido[2,3-d]azepin-3-amine (455 mg, 1.5 mmol), acetaldehyde (253 μl, 4.50 mmol) and 5% Pd/C (23.0 mg) in EtOH (18 ml) was subjected to H2 (50 psi) for 16 h at room temperature. The reaction mixture was filtered, concentrated under reduced pressure and purified by column chromatography to provide 280 mg (56%) of N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H NMR (CDCl3) δ 6.47 (1H), 4.03 (0.5H), 3.88 (5H), 3.71 (0.5H), 3.43 (1H), 3.64 (3H), 2.98 (2H), 1.20 (6H) ppm. A mixture of of N-ethyl-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine (331 mg, 1.00 mmol), K2CO3 (415 mg, 3.00 mmol), MeOH (13 ml) and H20 (2.7 ml) was stirred for 16h at room temperature. After removal of solvent under reduced pressure, the mixture was taken into aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to give 204 mg (87%) of N-ethyl-2-methoxy-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-3-amine. 1H-NMR (CDCl3) δ 6.48 (s, 1H), 3.87 (s, 3H), 3.80 (br s, 1H), 3.10-2.70 (m, 9H), 2.48 (br s, 1H), 1.26 (d, 3H), 1.24 (t, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: COc1ccc(N)cc1C(F)(F)F
Yield: 100 %

Procedure:
1-Methoxy-4-nitro-2-trifluoromethyl-benzene (10 g, 45 mmol) was hydrogenated in a Paar apparatus with shaking at 50 psi for 4 hours, with 1 g 10 wt % Pd/C. The reaction mixture was filtered through celite, and the filtrate was evaporated in vacuo to give 8.6 g 4-Methoxy-3-trifluoromethyl-phenylamine, 99%, as a solid.
Reaction SMILES: C(O)C.[CH:4]([C:7]1[CH:11]=[C:10]([N:12]2[CH2:43][CH2:42][C:15]3[N:16]=[C:17]([C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[C:24]([CH3:41])=[CH:25][N:26]5[S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[N:18]=[C:19](OC)[C:14]=3[CH2:13]2)[N:9]([CH3:44])[N:8]=1)([CH3:6])[CH3:5].[ClH:45].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:45][C:19]1[C:14]2[CH2:13][N:12]([C:10]3[N:9]([CH3:44])[N:8]=[C:7]([CH:4]([CH3:5])[CH3:6])[CH:11]=3)[CH2:43][CH2:42][C:15]=2[N:16]=[C:17]([C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24]([CH3:41])=[CH:25][N:26]3[S:31]([C:34]2[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=2)(=[O:32])=[O:33])[N:18]=1
Reactant: Cl
Reactant: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(c1cc(C(C)C)nn1C)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4cc(C(C)C)nn4C)C5)cccc32)cc1
Temperature: 87 °C

Procedure:
Ethanol (1.8 mL) was added to 6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (195 mg, 0.342 mmol) followed by 12 N aqueous hydrochloric acid (1.8 mL, 21.8 mmol). The mixture was then heated to 87° C. for ca. 15 hours. The mixture was then cooled to room temperature, diluted with dichloromethane, and slowly neutralized with saturated aqueous sodium bicarbonate. The resulting layers were separated and the aqueous layers were extracted an additional time with dichloromethane. The organic layers were combined and dried by passing through a phase separator and then concentrated. The resulting residue was diluted with 1,2-dichloroethane (3.5 mL) and place at 0° C. Then N-chloromethylene-N,N-dimethyl ammonium chloride (Vilsmeier reagent) (85 mg, 067 mmol) was added. The resulting mixture was then heated to 35° C. After 5 minutes at 35° C. the mixture was diluted with dichloromethane, and slowly neutralized with saturated aqueous sodium bicarbonate. The resulting layers were separated and the aqueous layers were extracted an additional time with dichloromethane. The organic layers were combined and dried over Na2SO4, filtered and concentrated to furnish 4-chloro-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine without the need for further purification. MS (ESI+) m/z 575.3 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:24][CH:23]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:19]([CH2:20][O:21][CH2:22]3)[CH2:18]2)[CH:9]=1.C1C(=O)N([I:50])C(=O)C1>C(#N)C>[CH3:40][Si:37]([CH3:39])([CH3:38])[CH2:36][CH2:35][O:34][CH2:33][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:41])[CH3:42])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:50])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:18][CH:19]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]([CH2:22][O:21][CH2:20]3)[CH2:24]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n1)C2
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C2COCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n1)C2
Reaction time: 0.5 h
Yield: 103.8 %

Procedure:
tert-butyl 7-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (1.1 g, 1.77 mmol) was suspended in acetonitrile (20 mL) and treated with NIS (396.4 mg, 1.77 mmol) at room temperature. The mixture was stirred for 30 min. Then solvent was evaporated off under reduced pressure, and the crude material was purified by column chromatography (SiO2, 0-40% hexane-EtOAc) to provide desired compound tert-butyl 7-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (1.37 g). HPLC-MS tR=3.37 min (UV254 nm). Mass calculated for formula C30H52IN5O5Si2 745.2; observed MH+ (LCMS) 746.0 (m/z).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH2:34][O:35]COC)=[CH:17][CH:16]=1.S(=O)(=O)(O)O>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:25][C:24]=2[CH2:34][OH:35])=[CH:17][CH:16]=1
Reactant: COCOCc1nc(-c2ccccc2)oc1CCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCc2oc(-c3ccccc3)nc2CO)cc1
Yield: 58.5 %

Procedure:
A mixture of 5-{2-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxyphenyl]ethyl}-4-methoxymethoxymethyl-2-phenyloxazole (3.80 g), 10% sulfuric acid (10 mL) and tetrahydrofuran (100 mL) was refluxed for 2 hrs and concentrated. Ethyl acetate was poured into the residue, and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (5-{2-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxyphenyl]ethyl}-2-phenyl-1,3-oxazol-4-yl)methanol as colorless crystals (2.03 g, yield 59%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). The crystals were recrystallized from ethyl acetate-hexane. melting point: 142-143° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[N:8]=[CH:7]2)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[N:8]=[CH:7]2
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3cc([N+](=O)[O-])ccc32)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3cc(N)ccc32)CC1
Yield: 97.9 %

Procedure:
tert-Butyl 4-(5-nitro-1H-indazol-1-yl)piperidine-1-carboxylate (6.78 mmol, 2.35 g) and 10% palladium on carbon (0.136 mmol, 0.144 g) were combined and stirred in ethanol (50 mL) under 5 bar hydrogen for 1 hour. The reaction mixture was filtered and the filtrate concentrated under vacuum to afford the title compound (2.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:32])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[C:20]([CH2:30][CH3:31])=[N:21][N:22]4[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24][C:23]=34)=[CH:14][CH:13]=2)[C:10]=1N)=[O:5])[CH3:2].C(ON=O)CC(C)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:32])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[C:20]([CH2:30][CH3:31])=[N:21][N:22]4[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[N:24][C:23]=34)=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nn(-c2ccc(Cc3c(CC)nn4c(C)cc(C)nc34)cc2)c1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccc(Cc3c(CC)nn4c(C)cc(C)nc34)cc2)nc1C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
5-Amino-1-[4-(2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenyl]-3-methyl-H-pyrazole-4-carboxylic acid ethyl ester (16) (923 mg, 1.76 mmol) was dissolved in 15 ml of THF and after addition of isoamylnitrite (620 mg, 5.29 mmol) the reaction mixture was stirred for 12 h at 70° C. The reaction mixture was evaporated under reduced pressure and purified by chromatography (10-50% EtOAc in cyclohexane, 30 min) to afford a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]([O:17]C)=[O:16])=[O:14])[CH:10]=2)[C:5]([CH3:20])([CH3:19])[CH2:4][CH2:3]1.[OH-].[K+]>CO>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]([C:15]([OH:17])=[O:16])=[O:14])[CH:10]=2)[C:5]([CH3:20])([CH3:19])[CH2:4][CH2:3]1
Reactant: COC(=O)C(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)C(=O)O)ccc21
Reaction time: 3 h
Yield: 82.5 %

Procedure:
A 25 mL round bottom flask equipped with a reflux condenser was charged with methyl (1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-7-ylcarbamoyl)formate 24 (0.200 g, 0.691 mmol), MeOH (10 mL) and KOH (0.078 g, 1.382 mmol). The reaction mixture was stirred for 3 h at reflux, evaporated to dryness and partitioned between EtOAc and H2O. 6N HCl was added to reach acidic pH and the organic layer was separated, washed with water, brine, dried with Na2SO4, filtered and concentrated on a rotary evaporator to give (1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-7-ylcarbamoyl)formic acid as a white solid 25 (0.157 g, 83% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=[O:22])[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2].[BH4-].[Na+]>C(Cl)Cl.CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:19][CH:20]=[CH:21][OH:22])[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COc1ccc(COc2ccc(C#N)cc2C=CC=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COc2ccc(C#N)cc2CC=CO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 3985.7 %

Procedure:
To 3-cyano-6-((4-methoxybenzyl)oxy)-1-(2-formylethenyl)benzene (2.30 g) in 100 mL solution of CH2Cl2/MeOH/H2O (2:7:1) was added NaBH4 (0.29 g) at 0° C. The resulting solution was stirred at 0° C. for 1 hour and concentrated. The resulting residue was diluted with 100 mL of saturated aqueous NaHCO3 and extracted with ethyl acetate (3×). The organic layer was dried, concentrated to afford 3-cyano-6-((4-methoxybenzyl)oxy)-1-(3-hydroxyprop-2-en-1-yl)benzene (92.3 g) as a yellow solid.