Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1.[Cl:33]Cl.O>C(O)(C)C>[ClH:33].[OH:1][C@H:2]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1.[OH:1][C@H:2]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:23][CH:24]=[O:25])[CH:17]=2)=[CH:7][CH:6]=1
Reactant: ClCl
Agent: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1O
Solvent: O
Solvent: CC(C)O
Product: Cl
Temperature: 5 °C
Reaction time: 16 h

Procedure:
In a 250 mL flask a hydrochloride salt of compound 1 having 1.52 equivalents of chlorine per mole of compound 1 (5.0 g, 9.8 mmol) was suspended in 1:1 isopropanol:water (79 mL). The slurry was heated in a stepwise fashion, from 50° C. to 70° C. in 5° C. increments, to dissolve the solid. The solution was allowed to cool and isopropanol (80 mL) was added in one portion. Additional isopropanol (80 mL) was added dropwise and crystal formation was observed after about 75 mL was added. The slurry was stirred at room temperature for 16 h. The crystals were isolated by filtration, washed with cold 85% isopropanol/water (10 mL) followed by isopropanol (10 mL) and dried under vacuum to yield the monohydrochloride salt of compound 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[CH3:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][N:28]2[CH2:33][CH2:32][CH:31]=[CH:30][C:29]2=[O:34])=[CH:25][CH:24]=1.[OH-].[K+]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh].O1CCOCC1>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][C:3]=1[CH:31]1[CH2:32][CH2:33][N:28]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:36][CH:35]=2)[C:29](=[O:34])[CH2:30]1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(CN2CCC=CC2=O)cc1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: [Cl-]
Solvent: C1=CCCC=CCC1
Solvent: C1COCCO1
Product: COc1ccc(CN2CCC(c3cc(C)c([N+](=O)[O-])cc3C)CC2=O)cc1
Temperature: 100 °C

Procedure:
In a 5 mL microwave reaction tube was added 2-(2,5-dimethyl-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (143 mg, 0.516 mmol, prepared from 1-bromo-2,5-dimethyl-4-nitrobenzene by standard protocol), 1-(4-methoxybenzyl)-5,6-dihydropyridin-2(1H)-one (56 mg, 0.26 mmol, prepared by following a similar procedure as reported by Lerchner etc. in Chem. Eur. J. 2006, 12, 8208), chloro(1,5-cyclooctadiene)rhodium (I) dimer (13 mg, 0.026 mmol), KOH (0.13 mL 1N aqueous solution) and dioxane (1.2 mL). The tube was degassed, filled with N2 and sealed. The reaction tube was then heated to 100° C. in a microwave reactor for 10 min. After the reaction tube was opened, the mixture was treated with saturated NH4Cl aqueous solution (3 mL) and extracted with EtOAc (3×4 mL). The organic layers were combined and concentrated. The residue was purified by flash column chromatography (silica gel, gradient 0%-70% EtOAc/hexane), to provide 4-(2,5-dimethyl-4-nitrophenyl)-1-(4-methoxybenzyl)piperidin-2-one. ESMS m/z 369.2 (M+H+).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[N:25]=[C:26]([NH:29][C:30](=[O:32])[CH3:31])[S:27][CH:28]=2)=[O:23])=[CH:17][CH:16]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:39]>ClCCl>[ClH:39].[NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]2[N:25]=[C:26]([NH:29][C:30](=[O:32])[CH3:31])[S:27][CH:28]=2)=[O:23])=[CH:19][CH:20]=1)=[O:11])[NH2:2]
Reactant: CC(=O)Nc1nc(C(=O)Nc2ccc(CCOC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(C(=O)Nc2ccc(CCOC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
To a suspension of 2-[4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}amino)phenyl]ethyl tert-butyl hydrazine-1,2-dicarboxylate (370.8 mg, 0.800 mmol) in anhydrous dichloromethane (4 ml) was added 4M hydrogen chloride dioxane solution (4 ml), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. The operation was performed twice to remove hydrogen chloride gas azeotropically. The residue was suspended in ethyl acetate, filtered, washed 3 times with ethyl acetate and 3 times with methanol, and dried under reduced pressure to give 2-[4-({[2-(acetylamino)-1,3-thiazol-4-yl]carbonyl}amino)phenyl]ethyl hydrazinecarboxylate hydrochloride (280.8 mg, 0.702 mmol, yield 87.8%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.[C:22]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH2:37]Cl)[O:34][N:33]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C)C.C(O)C>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:36]=[C:35]([CH2:37][N:18]3[CH2:17][CH2:16][N:15]([CH2:14][C@H:13]([OH:21])[CH2:12][O:11][C:8]4[CH:9]=[CH:10][C:4]5[S:3][C:2]([CH3:1])=[N:6][C:5]=5[CH:7]=4)[CH2:20][CH2:19]3)[O:34][N:33]=2)=[CH:30][CH:31]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1ccc(-c2noc(CCl)n2)cc1
Reactant: Cc1nc2cc(OC[C@@H](O)CN3CCNCC3)ccc2s1
Agent: CN(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@@H](O)CN3CCN(Cc4nc(-c5ccc(C(C)(C)C)cc5)no4)CC3)ccc2s1
Reaction time: 8 h

Procedure:
A solution of (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol, a compound of formula (6) (75 mg, 0.14 mmol), and 3-(4-tert-butylphenyl)-5-chloromethyl-1,2,4-oxadiazole (40 mg, 0.16 mmol) in 10% trimethylamine/ethanol, was heated to 73° C. and allowed to stir overnight. The solvent was evaporated under reduced pressure, and the resulting residue chromatographed by PTLC (3% methanol/methylene chloride). The resulting oil was diluted with methylene chloride and placed on the high Vac. overnight, to yield (2S)-3-[4-({3-[4-(tert-butyl)phenyl](1,2,4-oxadiazol-5-yl)}methyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol as a white solid (52 mg, 0.09 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\O)[CH:5]=[CH:4][N:3]=1.[CH3:29][C:30]([CH3:35])([CH3:34])[C:31](=[S:33])[NH2:32]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:33][C:31]([C:30]([CH3:35])([CH3:34])[CH3:29])=[N:32][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CC(C)(C)C(N)=S
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Yield: 53.3 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6, using N-{3-[(Z)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (1.00 g, 2.36 mmol) and 2,2-dimethylpropanethioamide (0.277 g, 2.36 mmol) the title compound was obtained (690 mg, 53.3% yield). MS (ESI): 521.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12]>>[C:11]([C:13](=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([OH:10])=[C:2]([OH:1])[CH:3]=1)[C:14]([NH2:16])=[O:15])#[N:12]
Reactant: N#CCC(N)=O
Reactant: O=Cc1ccc(O)c(O)c1
Product: N#CC(=Cc1ccc(O)c(O)c1)C(N)=O
Yield: 71 %

Procedure:
Reaction of 2.4 g (10 mmol) 3,4-dihydroxybenzaldehyde and 0.9 g (10.7 mmol) cyanoacetamide by the procedure described in Example 1 above gave 1.45 g (70% yield) of product as a yellow solid, m.p. 247° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+].Cl>CN1C(=O)CCC1>[CH2:10]([O:17][C:6]1[CH:5]=[C:4]([Cl:9])[CH:3]=[C:2]([Br:1])[CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Clc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 120 °C

Procedure:
To 1-bromo-3-chloro-5-fluorobenzene (25 g, 112 mmol) and benzyl alcohol (25 mL, 239 mmol) in NMP (200 mL) at room temperature was added sodium hydride (60% in mineral oil; 10.5 g, 263 mmol), and the reaction was heated to 120° C. for 10 hours. The mixture was acidified with 10% aqueous HCl and extracted with EtOAc to give the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Pb](SC#N)[S:12][C:13]#[N:14]>C1(C)C=CC=CC=1>[C:1]1([CH2:7][C:8]([N:14]=[C:13]=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CS[Pb]SC#N
Reactant: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)N=C=S
Temperature: 85 °C
Reaction time: 18 h

Procedure:
To a 250 mL round bottom flask was added phenylacetylchloride (15.0 g, 97.0 mmol) and toluene (70 mL) followed by lead (II) thiocyanate (25.7 g, 97.0 mmol). Upon completion of addition, the resulting suspension was stirred at 85° C. for 18 h. After this time, the resulting solids were separated by vacuum filtration, and the filtrate was concentrated by rotary evaporation to provide a residue. The residue was purified via silica gel chromatography (10% EtOAc:Hex) to yield the title compound as a pale yellow, non-viscous oil (12.2 g, 68.8 mmol, 71%). 1H NMR (400 MHz, CDCl3): δ ppm 7.41-7.30 (m, 3H), 7.29-7.23 (m, 2H), 3.85 (s, 2H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34]Cl)=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:25]=2[CH:42]=1>CC(N(C)C)=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]2[N:30]3[C:31]([CH2:34][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:32][N:33]=[C:29]3[CH2:28][N:27]=[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:25]=2[CH:42]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-fluoro-6-phenyl-1-(chloromethyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine to give 8-fluoro-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9]O>[O-2].[Fe+2].[O-2].[Zr+4].[O-2].[O-2].[Cr+3].[O-2].[O-2].[Cr+3].O>[C:6]1([OH:7])[C:5]([CH3:9])=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1ccccc1O
Reactant: CO
Agent: [Cr+3]
Agent: [Fe+2]
Agent: [Zr+4]
Solvent: O
Product: Cc1cccc(C)c1O

Procedure:
o-cresol, methanol and water in a molar ratio of 1:2,5:2,5 were reacted in the same way as in Example 1. The catalyst consisted of iron oxide, zirconium oxide, chromium oxide and lanthanium oxide in a molar ratio of 100:3:2:0,5. After working up, 2,6-xylenol was obtained with a selectivity of 98,2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[CH2:14]O.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.O.CS(C)=O>[N:26]([CH2:14][C:4]1[CH:5]=[C:6]([O:9][C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(OC(F)(F)F)cc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(OC(F)(F)F)cc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Dissolve (2-methoxy-5-trifluoromethoxy-phenyl)-methanol (4.49 g, 20.2 mmol) in DMF (40 mL) and treat with thionyl chloride (1.65 g, 22.6 mmol). Stir at RT for 2 h, then treat with potassium carbonate (5.57 g, 40.3 mmol), sodium azide (2.35 g, 36.1 mmol), and DMSO (40 mL). Stir the resulting mixture at RT overnight, then pour into water (100 mL) and extract with ether (3×100 mL). Combine the organic phases and wash with water (2×100 mL) and brine (100 mL). Dry the organic layer (MgSO4), filter, and concentrate to give the title compound (4.77 g, 96%) as a colorless oil that may be used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.14 (m, 2H), 6.87 (m, 1H), 4.34 (s, 2H), 3.85 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:3][CH2:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[C:7]([CH3:19])[CH:6]=1.O.[CH3:32]O>>[CH3:32][O:1][CH:2]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:22][CH:21]=1)[CH2:3][CH2:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:8]([O:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])=[C:7]([CH3:19])[CH:6]=1
Reactant: CO
Reactant: Cc1cc(CCC(O)c2ccc(OC(F)(F)F)cc2)cc(C)c1OC(C)(C)C(=O)O
Solvent: O
Product: COC(CCc1cc(C)c(OC(C)(C)C(=O)O)c(C)c1)c1ccc(OC(F)(F)F)cc1

Procedure:
This compound was prepared following the general procedure E, using a solution of 2-(4-(3-hydroxy-3-(4-(trifluoromethoxy)phenyl)propyl)-2,6-dimethylphenoxy)-2-methylpropanoic acid in a ⅓:⅔ mixture of water/methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[OH:9])[O:5][C:6]=1[CH3:7]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)=[O:9])[O:5][C:6]=1[CH3:7]
Reactant: Cc1cccc(C(O)c2cc(C)c(C)o2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C(=O)c2cc(C)c(C)o2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanol (1.4 g) was dissolved in chloroform (30 ml) to prepare a solution. Manganese dioxide (5.7 g) was added to the solution, and the mixture was stirred at room temperature overnight. Further, manganese dioxide (1.8 g) was then added thereto, and the mixture was stirred overnight. The reaction solution was filtered through Celite. The solvent was removed from the filtrate by distillation under the reduced pressure to give (4,5-dimethylfuran-2-yl)-(6-methyl-pyridin-2-yl)-methanone (815 mg, yield 58%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH:14]=[CH:15]C(OCC)=O)[O:12][C@@H:11]([N:21]2[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]([O:33][CH2:34][CH3:35])(=[O:32])[CH3:31]>[Pd]>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:31][C:30]([O:33][CH2:34][CH3:35])=[O:32])[O:12][C@@H:11]([N:21]2[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=C[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCOC(=O)CCC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a stirred solution of 3'-O-t-butyldimethylsilyl-5'-carbethoxymethylene-5'-deoxy-thymidine (4.24 g, 10 mmol) in ethyl acetate was added 200 mg of 10% Pd/C under nitrogen atmosphere. The nitrogen gas was removed by vacuum and hydrogen was introduced. This procedure was repeated twice, and stirring was continued under atmospheric pressure of hydrogen for 16 hours. The catalyst was filtered over a celite pad, and the solvent was removed in vacuo. The title compound was crystallized from hexane/ethyl acetate. The title compound was obtained in 95% yield.
Reaction SMILES: C1C=CC=CC=1.Br[C:8]1[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:8]1[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=Cc1ccc(Br)o1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccc(C=O)o1
Yield: 65 %

Procedure:
To a benzene (10 mL) solution of 5-bromo-2-furaldehyde 7 (350 mg, 2.0 mmol) and 2-methoxyphenylboronic acid 8 (304 mg, 2.0 mmol) was added tetrakis(triphenylphosphine)-palladium(0) (69.4 mg, 0.06 mmol) and sat. aq. K2CO3 solution (4.94 ml, 4.0 mmol) at 21° C. under an argon atmosphere. The reaction mixture was refluxed for 2 h. The mixture was then cooled and diluted with ethyl acetate (100 mL). The organic layer was washed with water (2×20 mL), then dried with brine and MgSO4 and concentrated in vacuo. Flash column chromatography on silica gel (hexane:ethyl acetate=20:1) of the residue afforded 5-(2-methoxyphenyl)-2-furaldehyde 9 in 65% yield (265 mg, yellow oil). 1H NMR (400 MHz, CDCl3): δ 9.65 (s, 1H), 8.05 (dd, J=8.0, 2.0 Hz, 1H), 7.39-7.35 (m, 1H), 7.33 (d, J=3.6 Hz, 1H), 7.14 (d, J=4.0 Hz, 1H), 7.07 (dt, J=7.2, 0.8 Hz, 1H), 7.00 (bd, J=8.0 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:17]=[CH:16][O:15][CH:14]=1.[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C:20](=[O:26])[CH2:19]2.[Cl-].[NH4+].Cl>CCOCC>[O:15]1[CH:16]=[CH:17][C:13]([C:20]2([OH:26])[CH:21]3[CH2:24][CH2:25][N:18]([CH2:23][CH2:22]3)[CH2:19]2)=[CH:14]1
Reactant: O=C1CN2CCC1CC2
Reactant: Brc1ccoc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OC1(c2ccoc2)CN2CCC1CC2
Temperature: -75 °C
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
A solution of n-butyllithium in hexane (14.2 mL, 1.5M, 21.3 mmol) was added dropwise to a solution of 3-bromofuran (2.2 mL, 23.9 mmol) in dry ether (40 mL) at -75° C. over 10 min. After 5 min., a solution of 3-quinuclidinone (2.66 g, 21.2 mmol) in dry ether (20 mL) was added, and the mixture was stirred at -75° C. for 4 hours. A solution of saturated aqueous ammonium chloride (1.5 mL) was added dropwise at -70° C., and the mixture was poured into 2.5M aqueous HCl and washed with ether. The aqueous layer was basified with 5M aqueous NaOH; the product was extracted with ether, dried (K2CO3), filtered, and concentrated in vacuo. Column chromatography on alumina, gradient eluted with CHCl3 →CHCl3 /MeOH (95:5), yielded 2.01 g (49%) of pure 3-(3-furyl)quinuclidin-3-ol, which was converted into the fumarate and recrystallized from acetone/MeOH; mp 207°-209° C.; Rf 0.21 in CHCl3 /MeOH on alumina. C11H15NO2.0.5C4H4O4 requires: C, 62.1; H, 6.8; N, 5.5. Found: C, 61.9; H, 6.9; N, 5.6.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:19]=1)(=[O:3])[CH3:2].[I:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1O.N1C=CC=CC=1>O1CCOCC1.CO>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]([C:16]([O:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[I:20])=[O:17])=[CH:11][C:10]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: Oc1ccccc1I
Reactant: CC(=O)OCc1ccc2oc(=O)c(C(=O)O)cc2c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)OCc1ccc2oc(=O)c(C(=O)Oc3ccccc3I)cc2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the suspension of the acid chloride of 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylic acid (4 mmol) obtained according to Pochet et al. (Bioorg. Med. Chem. 2000, 8, 1489) in anhydrous dioxane (10 mL) was added 2-iodophenol (5 mmol) and pyridine (0.4 mL). After 12 h stirring at room temperature, the solvent was evapotated under vacuum and the residue was suspended in methanol. The resulting precipitate was collected by filtration, washed with methanol and dried. The solid was crystallyzed in ethyl acetate (45%); mp: 156-158° C.
Reaction SMILES: C([NH:4][C:5]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:6]=1[O:7][CH2:8][CH:9]([OH:18])[CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])(=O)C>Cl>[NH2:4][C:5]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:6]=1[O:7][CH2:8][CH:9]([OH:18])[CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCC(O)CN1C(=O)CCC1=O
Agent: Cl
Product: Nc1cc([N+](=O)[O-])ccc1OCC(O)CN1C(=O)CCC1=O

Procedure:
2 g (0.0057 mol) of the 1-(2'-acetylamino-4'-nitrophenoxy)-3-succinimidopropan-2-ol obtained in the second step are heated for one hour, in a boiling water-bath, in 10 ml of hydrochloric acid (specific gravity=1.18), with stirring. After the reaction medium has been cooled, diluted and rendered alkaline, the expected product precipitates. It is filtered off, washed with water and recrystallised from ethanol. It melts at 200° C.
Reaction SMILES: Cl.O[C:3]1[N:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][N:7]=1.C[O-:22].[Na+]>CO>[OH:22][CH:9]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][CH:11]=1)[CH2:8][N:4]1[CH:5]=[CH:6][N:7]=[CH:3]1
Reactant: C[O-]
Reactant: CS(=O)(=O)Nc1ccc(CCn2ccnc2O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(O)Cn2ccnc2)cc1

Procedure:
Heat a mixture of 30.83 g (0.097 mole) of (±)-1-[2- hydroxy-2-[4-((methylsulfonyl)amino)phenyl]ethyl-1H-imidazole hydrochloride and 5.24 g (0.097 mole) of sodium methylate in 100 mL of methanol and filter hot through 300 g of alumina (Fisher, neutral, activity III). Wash the alumina with 20% methanol in methylene chloride (200 mL). Concentrate the filtrate in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]#[C:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>N1C=CC=CC=1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([S:35]([NH:26][C:22]2[CH:21]=[C:20]([C:19]#[C:18][C:17]3[CH:16]=[N:15][N:5]4[CH:6]=[C:7]([C:9]5[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=5)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=34)[CH:25]=[CH:24][N:23]=2)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3ccnc(N)c3)c12
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2cc(C#Cc3cnn4cc(-c5cnn(C)c5)cc(OC)c34)ccn2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}pyridin-2-amine (24 mg, 0.070 mmol) in pyridine (1400 μl), was added 3-methoxybenzenesulfonyl chloride (29 μl, 0.203 mmol). The reaction mixture was stirred for 72 hours at room temperature. The precipitated solid was filtered and the solid washed with 10 mL of dichloromethane. The solid was dried in vacuo to afford 3-methoxy-N-(4-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}pyridin-2-yl)benzenesulfonamide an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H); 8.34 (s, 1H); 8.26 (s, 1H); 8.06 (s, 1H); 7.99 (bs, 2H); 7.49-7.42 (m, 2H); 7.38 (s, 1H); 7.16-7.15 (m, 2H); 7.11 (s, 1H); 6.85 (bs, 1H); 4.07 (s, 3H); 3.87 (s, 3H); 3.79 (s, 3H). LRMS (ESI) calculated for C26H22N6O3S [M+H]+, 515.1; found 515.1.
Reaction SMILES: S(Cl)(Cl)=O.Cl.[NH2:6][C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH2:16](O)[CH3:17]>>[CH2:16]([O:14][C:13](=[O:15])[C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[NH2:6])[CH3:17]
Reactant: CCO
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H](N)CCCCN

Procedure:
Thionyl chloride (5.0 ml, 8.06 g, 68 mmoles) was dropped into 500 ml of icecooled dry ethanol. The stirred mixture was kept for 20 min at this temperature and L-lysine hydrochloride (20 g, 109 mmoles) was added.