Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[OH:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: OC(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
Under nitrogen atmosphere, a solution of 2-(4-chlorophenyl)-α-phenyl-3H-imidazo[4,5-b]pyridine-3-ethanol (9.44 g, 0.027 mole) in methylene chloride (50 ml) was added to a stirred suspension of pyridinium chlorochromate (8.75 g, 0.041 mole) in methylene chloride (100 ml) and allowed to stir at room temperature overnight. The reaction mixture was filtered. The residue was treated with boiling methylene chloride and filtered. The methylene chloride filtrate was treated with Florisil® and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from isopropyl alcohol. The crystals were collected by filtration, washed with isopropyl alcohol/water, and dried under high vacuum overnight at room temperature to give 5.0 g (54%) of title compound, mp. 211°-212.5° C.
Reaction SMILES: Cl.[I:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.O1CCOC[CH2:14]1>CO>[I:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: C1COCCO1
Reactant: O=C(O)Cc1ccc(I)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)Cc1ccc(I)cc1
Reaction time: 8 h

Procedure:
A 4M solution of HCl in dioxane (50 mL) was added to 2-(4-iodophenyl)acetic acid (10 g, 38.2 mmol) in MeOH (100 mL) and the reaction stirred overnight. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0-30% EtOAc in hexanes to afford methyl 2-(4-iodophenyl)acetate in 10.42 g (99%). LRMS: 276.0 (calc) 277.1 (found)(MH+)+.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.[N:17]([O-])=O.[Na+].[O-]S(S([O-])=O)=O.[Na+].[Na+].[OH-].[K+]>O.CCOCC>[ClH:1].[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1
Reactant: Nc1ccc(OCc2ccccn2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: NNc1ccc(OCc2ccccn2)cc1
Reaction time: 0.67 h
Yield: 129.7 %

Procedure:
4-(Pyridin-2-ylmethoxy)-phenylamine hydrochloride (95 g) was dissolved in water (1 L) at 0° C. and to this was added NaNO2 (26 g) in water (100 mL). The diazonium salt was allowed to form over 45 minutes and then it was poured slowly over 15 minutes into a rapidly stirred mixture of Na2S2O4 (350 g) in water (1 L) and ether (1 L) at 0° C. Stirring continued for 40 minutes then mixture was made basic using conc. KOH. After extraction using EtOAc (×2) the organic layers were washed with water, then brine, dried (MgSO4) and filtered. To this solution was added saturated HCl in EtOAc and a precipitated formed immediately. Collection of the solids by filtration followed by drying under vacuum provided the title compound as a tan solid (75 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([CH2:14]Br)[CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1.[CH3:17][NH:18][CH3:19]>C1COCC1.C(O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([CH2:14][N:18]([CH3:19])[CH3:17])[CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1
Reactant: CNC
Reactant: COC(=O)Cc1coc2ccc(CBr)cc12
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)Cc1coc2ccc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of (5-bromomethyl-benzofuran-3-yl)-acetic acid methyl ester (198 mg, 0.70 mmol) in THF (4.0 mL) is added a 5.6 M solution of dimethylamine in ethanol (1.0 mL). The resulting reaction mixture is stirred for 2 h at room temperature, filtered through a microfilter (25 μm) and the filtrate concentrated at reduced pressure to afford the title compound as a yellow oil (170 mg, 0.69 mmol, 98%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.56 (s, 1H), 7.45 (s, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 3.66 (s, 3H), 3.64 (s, 2H), 3.52 (s, 2H), 2.24 (s, 3H). MS (ES+): 248 (M(C14H17NO3)+H)+.
Reaction SMILES: [C:1]([N:5]1[C:18](=[O:19])[N:8]2[CH:9]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[NH:11][C:12](=O)[C:7]2=[N:6]1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[C:1]([N:5]1[C:18](=[O:19])[N:8]2[CH:9]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:12]([Cl:22])[C:7]2=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(=O)[nH]1
Product: CC(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(Cl)n1
Reaction time: 16 h

Procedure:
A solution of 5.90 g the product of Step D in phosphoryl chloride (100 mL) was heated to 110° C. After 16 h, the reaction mixture was cooled and the excess phosphoryl chloride was removed by distillation at reduced pressure (15 mm Hg). The residue was dissolved in chloroform and carefully poured onto 200 g of ice. After the ice had melted, the layers were separated and the aqueous was extracted with chloroform. The combined organic layers were washed with sat. sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to yield 2-tert-butyl-8-chloro-6-tert-butyl-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a yellow solid. MS (M+H+)=283.3.
Reaction SMILES: C(OC(=O)[NH:7][C@@:8]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:29][CH:28]=1)([CH3:24])[C@H:9]([O:11][P:12]([O:19]C(C)(C)C)([O:14]C(C)(C)C)=[O:13])[CH3:10])(C)(C)C>Cl.CO>[NH2:7][C@:8]([CH3:24])([CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:31][CH:32]=1)[C@H:9]([O:11][P:12](=[O:13])([OH:19])[OH:14])[CH3:10]
Reactant: CCCCCCCOc1ccc(CC[C@@](C)(NC(=O)OC(C)(C)C)[C@@H](C)OP(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Product: CCCCCCCOc1ccc(CC[C@@](C)(N)[C@@H](C)OP(=O)(O)O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
{(1R,2R)-2-(Di-tert-butoxy-phosphoryloxy)-1-[2-(4-heptyloxy-phenyl)-ethyl]-1-methyl-propyl}-carbamic acid tert-butyl ester (40 mg, 0.067 mMol) is dissolved in a saturated solution of HCl in methanol (5 ml) and stirred at RT for 24 hours. The solvent is evaporated under reduced pressure. Lyophilisation from dioxane/H2O (3:1) gives the title compound as a white, amorphous powder.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][OH:6]>C(Cl)Cl.O=[Mn]=O>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6]
Reactant: Cc1ccc(CO)cc1I
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1ccc(C=O)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1.0 mmol of this alcohol and 5.0 mmol of MnO2 in 5 mL of CH2Cl2 was stirred for 16 h at rt. Chromatography provided 3-iodo-4-methylbenzaldehyde.
Reaction SMILES: CC1[O:3][CH2:4][C:5]([CH2:25][O:26][P:27](=[O:38])([O:33]C(C)(C)C)[O:28]C(C)(C)C)([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:11][CH:10]=2)[N:6]=1.Cl>C(O)C>[NH2:6][C:5]([CH2:4][OH:3])([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:11][CH:10]=1)[CH2:25][O:26][P:27](=[O:28])([OH:33])[OH:38]
Reactant: CC1=NC(CCc2ccc(OCCCCCC(F)(F)F)cc2)(COP(=O)(OC(C)(C)C)OC(C)(C)C)CO1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CCc1ccc(OCCCCCC(F)(F)F)cc1)COP(=O)(O)O
Temperature: 85 °C
Reaction time: 2 h

Procedure:
To a solution of (2-Methyl-4-{2-[4-(6,6,6-trifluoro-hexyloxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol (300 mg, 0.80 mmol) and tetrazole (337.4 mg, 4.82 mmol, 6 eq., recrystallized from toluene) in dry THF (6 ml) is added 3-diethylamino-1,5-dihydrobenzo[e]-[1,3,2]dioxaphosphepine (433.5 μl, 1.56 mmol, 1.95 eq.). The reaction mixture is stirred under argon at room temperature for 3 h. Then, H2O2 (30%, 75 μl, 4.0 mmol, 5 eq.) is injected at 0° C. with vigorous stirring. The reaction mixture is stirred for further 30 min, followed by addition of saturated sodium thiosulfate solution (1 ml). The organic layer is separated and the aqueous phase is extracted with ether (3×20 ml). The combined organic extracts are washed with brine, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (AcOEt) affords phosphoric acid di-tert-butyl ester 2-methyl-4-{2-[4-(6,6,6-trifluoro-hexyloxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-ylmethyl ester as colorless oil. To a solution of phosphoric acid di-tert-butyl ester 2-methyl-4-{2-[4-(6,6,6-trifluoro-hexyloxy)-phenyl]-ethyl}-4,5-dihydro-oxazol-4-ylmethyl ester (33 mg, 0.050 mmol) in ethanol (2 ml) is added conc. HCl (2 ml). The reaction mixture is stirred at 85° C. for 2 hours, then concentrated to dryness. The residue is re-dissolved in AcOEt and precipitated with hexanes. The solid is filtered off, washed with dry ether and dried under vacuum to afford phosphoric acid mono-{2-amino-2-hydroxymethyl-4-[4-(6,6,6-trifluoro-hexyloxy)-phenyl]-butyl}ester as a colorless powder. MS (ESI−): 428.2 (MH−)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[C:18]([O:37][CH3:38])=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH3:36])[C:18]([O:37][CH3:38])=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1cc2c(c(CN3CCN(C(=O)OC(C)(C)C)CC3)c1OC)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc2c(c(CN3CCNCC3)c1OC)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-5,6-dimethoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.026 g, 0.050 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was azeotroped twice with toluene under reduced pressure. The residual solid was added with water, and then the mixture was adjusted to pH 9 with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-5,6-dimethoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.016 g, 76%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)C)#[N:2].C([SnH](CCCC)CCCC)CCC.[N-:33]=[N+:34]=[N-:35].[Na+]>C1(C)C=CC=CC=1.CO>[NH:2]1[C:1]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[C:6]3=[CH:13][C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[N:35][N:34]=[N:33]1
Reactant: CC(=C1C(=O)Nc2ccc(C#N)cc21)c1ccc[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[SnH](CCCC)CCCC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1Nc2ccc(-c3nnn[nH]3)cc2C1=Cc1ccc[nH]1
Reaction time: 8 h

Procedure:
A solution of 5-cyano-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one (100 mg, 0,42 mmol) in toluene was treated with tributyltin hydride (0.68 g, 2.1 mmol) and NaN3 (0.39 g, 2.52 mmol). The reaction mixture was refluxed overnight. Concentration afforded a residue which was dissolved in methanol and left at ambient temperature overnight. An orange-colored solid formed, which was filtered and dried in vacuo to afford 5-tetrazol-5-yl-3-[(pyrrol-2-yl)methylene]indolin-2-one; (29 mg) as an orange solid; 1H NMR (400 MHz, DMSO-d6) δ 6.22 (s, 1H), 6.90 (s, 1H), 7.08 (d, 1H), 7.20 (s, 1H), 7.80 (m, 1H), 7.84 (s, 1H), 8.14 (s, 1H), 11.22 (s, 1H) ppm.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:5]1([CH2:22][CH3:23])[CH2:20][CH2:19][N:8]2[C:9]3[C:14]([C:15]([CH3:16])=[C:7]2[C:6]1=[O:21])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=3)[CH3:4]>C(O)C>[CH2:22]([C:5]1([CH2:3][CH3:4])[CH2:20][CH2:19][N:8]2[C:9]3[C:14]([C:15]([CH3:16])=[C:7]2[CH:6]1[OH:21])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=3)[CH3:23]
Reactant: CCC1(CC)CCn2c(c(C)c3cc(OC)ccc32)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC1(CC)CCn2c(c(C)c3cc(OC)ccc32)C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
Sodium borohydride (380 mg, 10 mmol) was added portionwise to a solution of 8,8-diethyl-6,7,8,9-tetrahydro-2-methoxy-10-methylpyrido[1,2-a]indol-9-one (710 mg, 2.5 mmol) in ethanol (50 mL). The reaction mixture was stirred at 25° C. overnight. The solvent was evaporated in vacuo and the residue partitioned between 1% ammonium hydroxide (30 mL) and chloroform (49 mL). The separated organic layer was dried over MgSO4, filtered, and evaporated to afford 530 mg (74%) of the desired alcohol as a light amber oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.S(=O)(=O)(O)O.O.[I:15](O)(=O)(=O)=O.II.[OH-].[Na+]>II.O.C(O)(=O)C>[NH2:1][C:2]1[C:7]([I:15])=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: Nc1ccc(Br)cn1
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1I
Temperature: 25 °C
Yield: 76 %

Procedure:
2-Amino-5-bromopyridine (CAS No. 1072-97-5) (300 g) was dissolved in a mixed solvent consisting of 1000 ml of acetic acid and 200 ml of water, 30 ml of concentrated sulfuric acid were gradually dropped thereinto under stirring. Then, 79.1 g of periodic acid hydrate and 176 g of iodine were added thereto, followed by stirring at 80° C. for 4 hours. To the reaction mixture were added periodic acid hydrate (40 g) and iodine (22 g), followed by further stirring at 80° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured onto ice (3000 ml) and neutralized to pH 7.0 with 5N aqueous sodium hydroxide. The resulting crystals were collected by filtration, dissolved in a mixed solvent of ethyl acetate/diethyl ether, successively washed with aqueous sodium thiosulfate, water, 1N aqueous sodium hydroxide and brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated, to give 392 g of 2-amino-5-bromo-3-iodopyridine (yield: 76%). 2-Amino-5-bromo-3-iodopyridine (100 g) was gradually added to 300 ml of concentrated sulfuric acid under ice-cooling. After the reaction mixture was stirred at room temperature for 2 hours, it was ice-cooled again. 35 g of sodium nitrite were gradually added thereto, followed by stirring at room temperature for 3 days and nights. The reaction solution was poured onto ice (3000 ml) and neutralized to pH 4.0 with sodium hydroxide. The resulting crystals were collected by filtration, washed with water and warm air-dried at 60° C. for one day and night, to give 102 g (quantitative) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:29])[CH3:28])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.Cl.[C:36](OC(=O)C)(=[O:38])[CH3:37].C([O-])(=O)C.[Na+]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C.O>[C:36]([O:13][C:7]1[C:8]([CH3:12])=[C:9]2[C:4](=[C:5]([CH3:15])[C:6]=1[CH3:14])[O:3][C:2]([CH3:1])([CH2:16][CH2:17][CH2:18][C:19]([Cl:34])([CH3:33])[CH2:20][CH2:21][CH2:22][C:23]([Cl:32])([CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([Cl:30])([CH3:28])[CH3:29])[CH2:11][CH2:10]2)(=[O:38])[CH3:37]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl)O2
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CCCC(C)(Cl)CCCC(C)(Cl)CCCC(C)(C)Cl)O2
Reaction time: 2 h
Yield: 92.5 %

Procedure:
The product (5 g) obtained in Example 1, acetic acid (20 cc) and anhydrous zinc chloride (320 mg) are introduced, under an argon atmosphere, into a reactor. A solution (5 cc) of hydrochloric acid in acetic acid, containing 1.9 moles of hydrochloric acid per liter, is added. Thereafter, acetic anhydride (2.7 cc) is added over the course of 15 minutes. The temperature rises from 20° to 30° C. After 2 hours' stirring, water (10 cc), sodium acetate (800 mg) and ethyl acetate (100 cc) are added. After evaporation of the solvents, the residue is taken up in methylene chloride. After filtration over silica gel, 2,5,7,8-tetramethyl-2-(4',8',12'-trichloro-4',8',12'-trimethyl-tridecyl)-chroman-6-ol acetate (4.99 g) is obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[OH:10].C(=O)([O-])O.[Na+].[CH3:16][O:17][C:18](OC)([O:23]C)[C:19](OC)=O>>[OH:9][C:6]1[CH:7]=[CH:8][C:3]2[N:2]=[C:19]([C:18]([O:17][CH3:16])=[O:23])[O:10][C:4]=2[CH:5]=1
Reactant: Nc1ccc(O)cc1O
Reactant: COC(=O)C(OC)(OC)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1nc2ccc(O)cc2o1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of 4-aminobenzene-1,3-diol hydrochloride (i in Scheme 1) (0.50 g, 3.1 mmol) and sodium hydrogen carbonate (2.5 mg) in methyl trimethoxyacetate (2 mL) was stirred at 100° C. overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, methylene chloride/ethyl acetate=9/1) to afford methyl 6-hydroxybenzo[d]oxazole-2-carboxylate as a white solid (0.49 g, 82%). 1H-NMR (DMSO-d6, 300 MHz): δ 10.26 (s, 1H), 7.70 (m, 1H), 7.12 (m, 1H), 6.95 (m, 1H), 3.92 (s, 3H) ppm; MS (ESI): 194.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22]#[C:23][Si](C)(C)C)=[N:11][CH:10]=1.[OH-].[K+].[Cl-].[NH4+]>CO>[F:35][C:33]([F:34])([F:36])[C:31]1[CH:30]=[C:5]([CH:4]=[C:3]([C:2]([F:38])([F:37])[F:1])[CH:32]=1)[CH2:6][N:7]([CH3:29])[C:8](=[O:28])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([C:22]#[CH:23])=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(C#C[Si](C)(C)C)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CO
Product: C#Cc1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A mixture of 143 mg (0.261 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-6-trimethylsilanylethynyl-nicotinamide, 2.5 ml of a 1 M aqueous solution of potassium hydroxide and 2.5 ml methanol was stirred at room temperature for 1h. Acidifying to pH 5 with a saturated aqueous solution of ammonium chloride was followed by extraction with three portions of dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 97 mg (78%) of the title compound as a light brown solid.
Reaction SMILES: [CH2:1]([C:4]1[N:9]2[N:10]=[CH:11][C:12]([C:13]([O:15]CC)=[O:14])=[C:8]2[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([C:4]1[N:9]2[N:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[C:8]2[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1cccc2c(C(=O)OCC)cnn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cccc2c(C(=O)O)cnn12
Temperature: 100 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To 0 46 g (1.98 mmol) of ethyl 7-propylpyrazolo[1,5-a]pyridine-3-carboxylate, 8 ml of 2.5N aq. NaOH solution and 5 m; of ethanol were added, followed by stirring at 100° C. for 3 hours. After the reaction, post treatments were conducted in a similar manner to the syntheses of the 5-methyl and 2,7-dimethyl derivatives so that 0.37 g (1.81 mmol) of crystals of the title compound were obtained (Yield: 91%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([N:16]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH2:18][CH2:17]3)=[CH:14][S:13][C:12]=2[CH:28]=1>C(OCC)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([N:16]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:18][CH2:17]3)=[CH:14][S:13][C:12]=2[CH:28]=1
Reactant: N#CCCCN1CCCN(c2csc3cc(F)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCCCCN1CCCN(c2csc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
Add over 30 min, at room temperature, a solution of LiAlH4 in diethyl ether (1M, 72.5 mL) to a solution of 4-[4-(6-fluoro-benzo[b]thiophen-3-yl)-[1,4]diazapan-1-yl]butyronitrile (Example 5) (11.5 g, 36.2 mmol) in dry diethyl ether (200 mL). Heat the solution to reflux for 5 h. After that time, allow the solution to cool to room temperature and carefully quench the reaction with water and aqueous sodium hydroxide solution. Separate the phases, and re-extract the aqueous phase with EtOAc. Dry the combined organic phases over MgSO4 and remove the solvent under vacuum. Purify the crude product by column chromatography (CH2Cl2/MeOH/NH4OH 9:2:0.25) to obtain 8.9 g of a colorless oil LC/MS, (LiChrospher 5μ, RP-18, 250 mm CH3CN/Water(0.05% TFA)-gradient 2%→98% (20 min), Flow: 0.75 mL/min), tR=7.79 min, m/z=321.3.
Reaction SMILES: CC([O-])(C)C.[Na+].Br[C:8]1[CH:9]=[C:10]([Cl:16])[C:11]([O:14][CH3:15])=[N:12][CH:13]=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][C@H:26]([O:29][C:30]2[C:31]3[CH2:39][NH:38][CH2:37][CH2:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCOC(C)=O>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][C@H:26]([O:29][C:30]2[C:31]3[CH2:39][N:38]([C:8]4[CH:13]=[N:12][C:11]([O:14][CH3:15])=[C:10]([Cl:16])[CH:9]=4)[CH2:37][CH2:36][C:32]=3[N:33]=[CH:34][N:35]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1ncc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ncnc3c2CNCC3)C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)OC(C)(C)C)C4)c3C2)cc1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 50.4 %

Procedure:
X-Phos (0.073 g, 0.154 mmol), Pd2(dba)3 (0.100 g, 0.110 mmol), NaOtBu (0.395 g, 4.11 mmol) and 5-bromo-3-chloro-2-methoxy-pyridine (0.732 g, 3.29 mmol) were combined and flushed under a stream of argon for 10 min. To this mixture, a solution of (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 7) (2.15 g, 6.72 mmol) in THF (6 mL) was added at rt and the reaction mixture was stirred at 90° C. for 3 h. The reaction was cooled down to rt, EtOAc was added, the mixture filtered through a celite pad and concentrated under vacuum. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 99/1 to 95/5) gave (S)-3-[6-(5-chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow foam (0.766 g, 60% yield). LCMS: [M+H]+=462.1, Rt(3)=1.84 min