Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[C:40]([F:43])([F:42])[F:41].[BrH:44]>C(#N)C.CCOC(C)=O.O.[Cu]Br>[Br:44][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31]([NH:33][CH3:34])=[O:32])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[C:40]([F:43])([F:42])[F:41]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(F)(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(C(F)(F)F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
Sodium nitrite (0.18 g, 2.55 mmol) was added to a 0° C. solution of 6-(N-(4-amino-3-(trifluoromethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (1.3 g, 2.32 mmol) in acetonitrile (14 ml) and aq HBr (48%) (14 mL). The reaction mixture was stirred for 30 min at 0° C. and copper (I) bromide (0.40 g, 2.78 mmol) was added. The reaction mixture was stirred at 60° C. for 1 h and diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (1.06 g, 73%) as a white foam. LCMS (m/z, ES+)=625.2, 627.2 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:9][C:7]=2[CH:8]=1.[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31](O)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:24]2[C:28]3[CH:29]=[CH:30][C:31]([O:1][CH2:2][CH2:3][C:4]4[O:5][C:6]5[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:7]=5[CH:8]=4)=[C:32]([CH2:33][CH2:34][CH3:35])[C:27]=3[O:26][CH:25]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Reactant: COC(=O)Cc1ccc2oc(CCO)cc2c1
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3o2)ccc2c(-c3ccccc3)coc12

Procedure:
Using the procedure from Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)benzofuran-5-acetate and 3-phenyl-6-hydroxy-7-propylbenzofuran as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:5][CH:4]1[C:6](O)=[O:7].[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:6]([CH:4]4[CH2:5][CH:3]4[C:2]([F:10])([F:9])[F:1])=[O:7])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C(O)C1CC1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C3CC3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-trifluoromethylcyclopropanecarboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (30.9% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.98, 7.00, 3.97-3.57, 2.20, 1.65, 1.50, 1.26, 0.75, 0.46, 0.09. MS (ES+) m/z 412 (M+1).
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([SH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:9]([S:16][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Fc1ncccc1I
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Ic1cccnc1SCc1ccccc1

Procedure:
A solution of 34.0 g (0.15 mol) of 2-fluoro-3-iodopyridine and 18.6 g (0.15 mol) of benzylmercaptan in 250 ml of acetonitrile is heated under reflux with 22.8 g (0.165 mol) of potassium carbonate for 8 h. The mixture is cooled, the solvent is removed on a rotary evaporator, the residue is taken up in dichloromethane and the organic phase is washed with water. After drying with sodium sulfate, evaporating and distilling the oily residue in vacuo, 37.3 g (76% of theory) of 2-benzylthio-3-iodopyridine of boiling point 150°-153° C. at 0.1 mbar are obtained.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[C:6]([NH2:21])[CH:5]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+].Cl>C1COCC1.CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:22])=[CH:5][C:6]=2[NH:21][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:13]1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(C=Cc2n[nH]c3ccccc23)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)c(NC(=O)c2ccccc2)c1
Reaction time: 4 h
Yield: 91.3 %

Procedure:
A solution of 3-amino-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid methyl ester (0.30 g, 1.0 mmol) obtained in Step 1 of Example 217 and triethylamine (0.43 ml, 3.1 mmol) in THF (10 mL) was added with benzoyl chloride (0.13 mL, 1.1 mmol) followed by stirring for 4 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and concentrated under reduced pressure to obtain crude product. Further, the product was dissolved in methanol (20 mL) and the solution was added with 2 mol/L aqueous sodium hydroxide solution (5.0 mL), followed by stirring at 60° C. for 1 hour. The reaction mixture was acidified by hydrochloric acid (6 mol/L) and the precipitated crystal was collected by filtration to obtain (E)-4-[2-(1H-indazol-3-yl)vinyl]-3-(benzoylamino)benzoic acid (0.35 g, 89%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[NH2:27][C:28]([CH3:34])([CH3:33])[CH2:29][CH2:30][CH2:31][OH:32]>CN(C=O)C>[OH:32][CH2:31][CH2:30][CH2:29][C:28]([NH:27][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:34])[CH3:33]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)CCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CCCO)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.7 %

Procedure:
5-Cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) was suspended in DMF (3 mL). Mukaiyama Reagent (CAN 878-23-9, 233.8 mg, 0.85 mmol), DIEA (0.31 mL, 2.24 mmol) and 4-amino-4-methyl-pentan-1-ol (CAN 85054-53-1, 101.33 mg, 0.64 mmol) were added and the reaction mixture was stirred at room temperature for 12 hours. The mixture was extracted with ethyl acetate and water; the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by reverse phase preparative HPLC (Xterra-RP18, 10 μ, 19×250 mm/acetonitrile/10 mM ammonium acetate in water) to give the desired product (100 mg, 70.26%) as colorless sticky liquid; LC-MS (UV peak area, ESI) 96.12%, 334.0 (M+H).
Reaction SMILES: [CH2:1]([O:19][C:20]([O:22][CH2:23][C:24](=[CH2:27])[CH2:25][OH:26])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].BrCCCCCC(O)=O.[Br:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45]>>[CH2:1]([O:19][C:20]([O:22][CH2:23][C:24](=[CH2:27])[CH2:25][O:26][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][Br:37])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=C(CO)COC(=O)OCCCCCCCCCCCCCCCCCC
Reactant: O=C(O)CCCCCCBr
Agent: O=C(O)CCCCCBr
Product: C=C(COC(=O)CCCCCCBr)COC(=O)OCCCCCCCCCCCCCCCCCC

Procedure:
Following the procedure described in Preparation 9, but replacing 3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with 3-octadecyloxycarbonyloxy-2-methylenepropan-1-ol and 6-bromohexanoic acid with 7-bromoheptanoic acid, the desired product was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([OH:26])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:28]1[C:32]2[CH:33]=CC=C[C:31]=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C(N)(C)C>CN(C=O)C>[CH:32]([NH:28][C:24]([CH:12]1[CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:26])([CH3:33])[CH3:31]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: CC(C)NC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid 47-1 (0.40 g, 1.10 mmol), 1-hydroxybenzotriazole (0.20 g, 1.32 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.27 g, 1.43 mmol), 4-methylmorpholine (0.0.44 g, 4.39 mmol) and isopropyl amine (0.071 g, 1.21 mmol) were dissolved in DMF and stirred at 25° C. for 18 hours. The DMF was then removed under reduced pressure and the residue partitioned between ethyl acetate and dilute aqueous KHSO4. The aqueous phase was drawn off and the organic layer was washed with dilute aqueous NaHCO3, brine, dried, filtered and evaporated to afford 47-2.
Reaction SMILES: [Si:1]([O:8][C:9]1([O:16][C@@H:15]([CH3:17])[C@@H:13]([OH:14])[C@@H:12]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:11]1)[OH:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC(C)=CC=1C.[Br:34][CH2:35][C:36](Br)=[O:37].ClCl>C(Cl)Cl.O>[Si:1]([O:8][C:9]1([O:16][C@@H:15]([CH3:17])[C@@H:13]([O:14][C:36](=[O:37])[CH2:35][Br:34])[C@@H:12]([NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23])[CH2:11]1)[OH:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H]1OC(O)(O[Si](C)(C)C(C)(C)C)C[C@H](NC(=O)C(F)(F)F)[C@@H]1O
Reactant: O=C(Br)CBr
Agent: ClCl
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1OC(O)(O[Si](C)(C)C(C)(C)C)C[C@H](NC(=O)C(F)(F)F)[C@@H]1OC(=O)CBr
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a stirred solution of 1-t-butyl dimethylsilyloxy-3-trifluoroacetamido-2,3,6-trideoxy-L-lyxohexopyranose (81 mg, 0.18 mmol) in CH2Cl2 (2 ml) at 0° C. were added collidine (47 μl, 0.36 mmol), and bromoacetylbromide (24 μl, 0.27 mmol). After 1 hour, the reaction mixture was worked up with CH2 Cl2 and water. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to give the titled compound (76 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[CH2:9]O.P(Br)(Br)[Br:13]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[CH2:9][Br:13]
Reactant: CC1(C)CCC(C)(C)C1CO
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Product: CC1(C)CCC(C)(C)C1CBr
Temperature: 0 °C

Procedure:
2,2,5,5-Tetramethyl-1-cyclopentylmethanol is dissolved in benzene and stirred at 0° C. under argon. A solution of phosphorus tribromide in benzene is added and the mixture is stirred for 2 hours and then heated to 60° C. for 4 hours. The mixture is cooled, poured into ice and extracted with ether. The organic layer is washed with saturated NaHCO3, dried over MgSO4 and evaporated to yield 2,2,5,5-Tetramethyl-1-cyclopentylmethyl bromide.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:3]1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:47])([F:46])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:34][CH:33]=1.CN(P(N(C)C)(N(C)C)=O)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:11]([O:10][C:8]([N:6]1[C@@H:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:3][C:2](=[O:1])[C@H:7]1[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([F:46])([F:47])[C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])=[CH:36][CH:37]=1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)C(F)(F)c1ccc(CBr)cc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)C(F)(F)c1ccc(C[C@@H]2C(=O)O[C@H](c3ccccc3)[C@H](c3ccccc3)N2C(=O)OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution at −78° C. of benzyl (2R, 3S)-(−)-6 oxo-2,3 diphenyl-4 morpholine carboxylate (10.5 g) and tert butyl 2-{4-(bromomethyl)phenyl}-2,2-difluoroacetate (6.2 g) and HMPA 55 mL in THF 550 ml. was added LiHMDS (28 mL, 1 M in THF) over a period of 1 hour 20 minutes. The reaction mixture was stirred further at −78° C. for 1 hour.
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[C:18]2[C:25]([CH3:26])=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)CC)C>C(O)(C)C>[CH3:26][C:25]1[C:18]2[CH:17]([N:10]3[CH2:9][CH2:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]3)[NH:22][CH:21]=[N:20][C:19]=2[NH:23][CH:24]=1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c[nH]c2c1C(N1CCC(C(=O)O)(c3ccccc3)CC1)NC=N2
Temperature: 180 °C
Yield: 62 %

Procedure:
To a solution of 4-phenylpiperidine-4-carboxylic acid from step A (0.74 g, 3.1 mmol) in isopropanol (10 mL), was added 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.52 g, 3.1 mmol) and triethylamine (1.0 mL, 9.8 mmol). The reaction mixture was heated at 180° C. for 180 minutes under microwave condition, and then concentrated under vacuum. The residue was dissolved in ice water and neutralized to pH 4 by addition of 1 N aq. HCl. The product was isolated by filtration and dried under vacuum for 3 hours at 65° C. to give the title compound (62%) as a brown solid. MS (ES+) [M+H]+=336.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C([Li])CCC.[CH3:17][N:18](C=O)[CH3:19].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7]([CH2:17][NH:18][CH3:19])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1csc2ccc(Cl)cc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CNCc1sc2ccc(Cl)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.4 %

Procedure:
To a solution of 5-chloro-3-methyl-benzo[b]thiophene (4.98 g, 27.3 mmol) in THF (50 mL) at −40° C. was added n-butyllithium (18.7 mL of a 1.6 M solution in hexanes, 30.0 mmol) dropwise. The resulting yellow solution was stirred for 1 h and then DMF (6.3 mL, 81.9 mmol) was added in one portion. The solution was warmed slowly to room temperature and stirred overnight. Saturated aqueous NH4Cl was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6.62 g, 89%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.85 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.0 Hz, 1H), 2.74 (s, 3H).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[C:15]1(C=CC(O)=C[CH:17]=1)O.[C:23]1(C)C=CC(S(O)(=O)=O)=C[CH:24]=1>C(OC=C)(=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH:15]([O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:14][CH:23]=[CH2:24])=[O:13])=[CH2:17]
Reactant: Oc1ccc(O)cc1
Reactant: O=C(O)CCCCCCCCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: C=COC(C)=O
Solvent: CCOC(C)=O
Product: C=COC(=O)CCCCCCCCC(=O)OC=C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
15 g (74.2 mmol) of sebacic acid, 0.66 g (2.06 mmol) of mercury(II)acetate, and 0.12 g of hydroquinone were precharged in 75 ml of vinyl acetate into a 250 ml three-necked flask and stirred for 20 minutes under argon. Then, 0.09 g (0.01 mol) of p-toluenesulfonic acid were added as a catalyst, and the reaction mixture was refluxed for 4 hours. After cooling down to room temperature, the obtained solution was diluted with 200 ml ethyl acetate and extracted with 150 ml 2N NaOH. The organic phase was dried over Na2SO4, and the volatile components were removed on a rotary evaporator. Purification by flash column chromatography on silica gel (PE:EE=10:1) yielded 8.9 g (47% of th.) of a colorless liquid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:5]([OH:14])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:20]Br>C(O)(=O)C.O>[Br:20][C:4]1[CH:3]=[C:2]([F:1])[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[OH:14]
Reactant: BrBr
Reactant: O=C(O)c1c(F)ccc(O)c1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1c(F)cc(Br)c(O)c1[N+](=O)[O-]
Reaction time: 14 h
Yield: 74.7 %

Procedure:
6-Fluoro-3-hydroxy-2-nitrobenzoic acid (22 mg, 0.11 mmol) was dissolved in acetic acid (2 mL). Sodium acetate (10 mg, 0.12 mmol) and Br2 (10 μL, 0.19 mmol) was added and the reaction mixture was left at room temperature for 14 h. The temperature was raised to 50° and the reaction was continued for another 4 h. Evaporation gave a residue which was dissolved in water, and after adjustment of the pH the aqueous phase was extracted with EtOAc. Washing of the organic phase with water and evaporation gave a crude product which was purified by flash chromatography on SiO2. Eluation with toluene-EtOAc-HOAc afforded the product (23 mg). 1NMR (CD3OD): δ8.0 (d, J=8.7, 1H); MS (EI, 70 eV): m/z (rel. int.) 279/281 (M+, 40/38)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].Cl[C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl.O>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: OCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
A mixture of 3-amino-1-propanol (51 ml, 0.66 mol), chlorotriphenylmethane (184 g, 0.66 mol) and triethylamine (92 ml, 0.66 mol) in dichloromethane (1000 ml) was stirred at room temperature for 18 hours. The reaction mixture was diluted with water and the layers separated. The aqueous phase was extracted with further dichloromethane (2×) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was triturated well with diisopropyl ether, and the resulting solid was filtered and dried. This solid was then triturated with methanol, the suspension filtered, and the filtrate concentrated under reduced pressure, to give the title compound as a white solid, 139.1 g, 66% yield.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[C:21]3[N:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)c1
Yield: 61.7 %

Procedure:
Reaction of 1-(3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (126 mg, 62%). MS (ISP) 409.2 [(M+H)+]; mp 171° C.
Reaction SMILES: [CH:1]([C@@:9]1([OH:25])[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>>[C:31]1(=[O:32])[N:27]([CH:14]([OH:15])[C@H:13]2[O:12][C@@H:11]([N:16]3[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]3=[O:18])[CH2:10][C@:9]2([CH:1]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[OH:25])[C:28](=[O:37])[C:29]2=[CH:36][CH:35]=[CH:34][CH:33]=[C:30]12
Reactant: Cc1cn([C@H]2C[C@@](O)(C=Cc3ccccc3)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)N1O
Product: Cc1cn([C@H]2C[C@@](O)(C=Cc3ccccc3)[C@@H](C(O)N3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Yield: 97 %

Procedure:
Mitsunobu reaction of 3'-C-styrylthymidine with N-hydroxyphthalimide gave 97% yield of 5'-C-phtalimido-3'-C-styrylthymidine as a white solid. Anal.: C26H23N3O6Calcd.: C% 65.95; H% 4.89; N% 8.87; Found: C% 65.69; H% 5.11; N% 8.59.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)[C:2]#[CH:3].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:14]=O>O1CCOCC1>[N:9]1([CH2:14][C:3]#[C:2][CH2:1][N:4]2[CH:8]=[CH:7][N:6]=[CH:5]2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C#CCn1ccnc1
Reactant: C1CCNC1
Reactant: C=O
Solvent: C1COCCO1
Product: C(#CCn1ccnc1)CN1CCCC1
Temperature: 50 °C
Yield: 68.7 %

Procedure:
A mixture of 1-(2-propynyl)-1H-imidazole (2.5 g, 0.023 mol), pyrrolidine (2.0 g, 0.026 mol), paraformaldehyde (0.85 , 0.028 mol) and cuprous chloride (30 mg) in dioxane (20 mL) was heated at 50° C. for 4 h. The solvent was evaporated and the residual oil was dissolved in chloroform, filtered, and chromatographed on silica gel to give 2.99 g of 1-[4-(pyrrolidinyl)-2-butynyl]-1H-imidazole as an oil.