Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]([CH2:25][OH:26])[C@@H:5]([OH:24])[C@H:6]([OH:23])[C@@H:7](OS(C)(=O)=O)[C@@H:8]([OH:17])[C@@H:9]([OH:16])[CH2:10]OS(C)(=O)=O)=[N+]=[N-].C(OCC)(=O)C.CO.C([O-])(=O)C.[Na+]>O.[Pd]>[OH:26][CH2:25][C@@H:4]1[N:1]2[C@H:7]([C@@H:8]([OH:17])[C@@H:9]([OH:16])[CH2:10]2)[C@@H:6]([OH:23])[C@@H:5]1[OH:24]
Reactant: CS(=O)(=O)OC[C@H](O)[C@H](O)[C@H](OS(C)(=O)=O)[C@@H](O)[C@H](O)[C@H](CO)N=[N+]=[N-]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: OC[C@H]1[C@@H](O)[C@H](O)[C@H]2[C@@H](O)[C@@H](O)CN21

Procedure:
7-Azido-7-deoxy-1,4-di-O-methanesulphonyl-L-threo-L-talo-octitol (Qi, 1.6 g, 3.78 mmol) was dissolved in water (30 ml) and was treated with 10% palladium on carbon (400 mg) under an atmosphere of hydrogen for 16 h. T.l.c analysis (ethyl acetate:methanol, 9:1) indicated the disappearance of starting material (Rf 0.75) and the presence of a more polar product (Rf 0.05). Palladium was removed by filtration and the filtrate was treated with sodium acetate (930 mg, 11.34 mmol) at 60° C. for 16 h. The reaction mixture was cooled and the solvent removed in vacuo. The crude brown oil was purified by ion-exchange chromatography (Dowex 50WX8-100, eluting with 2M ammonium hydroxide) to afford (1R,2R,3S,6S,7R,7aR)-3-(hydroxymethyl)-1,2,6,7-tetrahydroxypyrrolizidine [3,7-diepi-Casuarine] Qj as a brown glass (671 mg, 87%): δH (D2O) 2.81-2.92 (m, 2H, H-5, H-5a), 3.16 (dd, 1H, J3,2 5.91 Hz, J3,8 10.74 Hz, H-3), 3.30 (app t, 1H, J 3.78 Hz, H-7), 3.76 (dd, 1H, J8,8a 6.35 Hz, H-8), 3.87 (dd, 1H, H-8a), 4.01 (d, 1H, J2,1 3.55 Hz, H-2), 4.04-4.12 (m, 2H, H-6, H-7), 4.29 (app t, 1H, H-1); δC (D2O) 49.32, 57.29, 63.78, 70.41, 72.59, 72.65, 74.47, 78.25; [α]D −21.1 (c 0.5, H2O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][NH:10][C:11](=[O:21])[C:12]1[C:17](I)=[CH:16][CH:15]=[N:14][C:13]=1[O:19][CH3:20].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:19][CH3:20])[C:12]=2[C:11](=[O:21])[NH:10]1
Reactant: COc1nccc(I)c1C(=O)NNc1c(F)cccc1F
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1nccc2c1c(=O)[nH]n2-c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
To a solution of N′-(2,6-difluorophenyl)-4-iodo-2-methoxynicotinohydrazide (1.32 g) in DMSO (20 mL) were added L-proline (75.0 mg) and potassium carbonate (901 mg) at room temperature. Copper(I) iodide (62.1 mg) was added thereto under nitrogen atmosphere at 60° C., and the mixture was stirred overnight at 60° C. The reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (278 mg).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH2:33][C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:42].[Li+]>C(COC)OC>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:42])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:41])(=[O:31])=[O:32])=[CH:26][CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(S(=O)(=O)Cc3c(Cl)cccc3Cl)cc2)C(=O)O1
Agent: [Li+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(S(=O)(=O)Cc2c(Cl)cccc2Cl)cc1)C(=O)O

Procedure:
In analogy with Example 5e), 6.7 g (10.83 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-{[p-(2,6-dichlorobenzylsulfonyl)phenyl]methyl}dihydrofuran-2-(3H)-one in 170 ml of dimethoxyethane are hydrolysed with 43.3 ml of a 1 M lithium hydroxide solution (RT, 17 h). Partitioning between 3× methylene chloride, NH4Cl/citric acid solution and saline, and stirring the crude product in ether, affords the title compound: tRet (II)=15.5 min.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]([C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[CH:41]=[CH:40][N:39]=[C:38]3[CH:42]=[C:43]([C:45]([N:47]4[CH2:51][CH2:50][C@@H:49]([O:52][CH3:53])[CH2:48]4)=[O:46])[S:44][C:37]=23)=[CH:31][CH:30]=1)[C:25]([NH:27][CH3:28])=[O:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:53][O:52][C@@H:49]1[CH2:50][CH2:51][N:47]([C:45]([C:43]2[S:44][C:37]3[C:38](=[N:39][CH:40]=[CH:41][C:36]=3[O:35][C:32]3[CH:33]=[CH:34][C:29]([C:24](=[O:23])[C:25]([NH:27][CH3:28])=[O:26])=[CH:30][CH:31]=3)[CH:42]=2)=[O:46])[CH2:48]1
Reactant: CNC(=O)C(O)c1ccc(Oc2ccnc3cc(C(=O)N4CC[C@@H](OC)C4)sc23)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)C(=O)c1ccc(Oc2ccnc3cc(C(=O)N4CC[C@@H](OC)C4)sc23)cc1
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of Dess-Martin reagent (48 mg, 0.114 mmol) in 1.5 mL of CH2Cl2 cooled to 0° C., was added dropwise a solution of 2-hydroxy-2-{4-[2-((R)-3-methoxy-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-phenyl}-N-methyl-acetamide (Example 77) (42 mg, 0.095 mmol) in 1.5 mL of CH2Cl2. The mixture was stirred at 0° C. to room temperature for one hour. Saturated aqueous NaHCO3 solution was added, and the mixture was extracted with CH2Cl2 and a small amount of MeOH. The combined organic phase was dried over Na2SO4, concentrated, and purified by flash column chromatography eluting with EtOAc:CH2Cl2:MeOH (1:1:0.04) to provide 30 mg white solid as the compound of Example 78. 1H NMR (300 MHz, CD3OD) δ 8.47 (d, 1H, J=5.47 Hz), 8.17 (d, 2H, J=8.66 Hz), 7.28 (d, 2H, J=8.66 Hz), 7.78–7.62 (m, 1H), 6.81 (d, 1H, J=5.47 Hz), 4.08–3.76 (m, 5H), 3.75–3.52 (m, 3H), 2.78 (s, 3H), 2.30–1.97 (m, 2H). LCMS (ESI+) [M+H]/z Calc'd 440, found 440. Anal. (C22H21N3O5S.0.4CH2Cl2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:19]=[C:20]([NH:24][C:25]([CH:27]2[CH2:30][CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:22][CH:23]=1)=O>>[CH:27]1([C:25]([NH:24][C:20]2[CH:19]=[C:18]([C:16]3[N:3]4[N:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]4[N:1]=[CH:14][CH:15]=3)[CH:23]=[CH:22][CH:21]=2)=[O:26])[CH2:28][CH2:29][CH2:30]1
Reactant: CN(C)C=CC(=O)c1cccc(NC(=O)C2CCC2)c1
Reactant: CCOC(=O)c1c[nH]nc1N
Product: CCOC(=O)c1cnn2c(-c3cccc(NC(=O)C4CCC4)c3)ccnc12

Procedure:
A 0.78 g portion of 3-amino-4-carboethoxypyrazole ard 1.36 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]cyclobutanecarboxamide were reacted as described in Example 13, giving 1.52 g of the desired product, mp 123°-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20](CC3C=CC=CC=3)[CH3:21])[C:12]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH2:34]([O:41][C:42](Cl)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([C:42]([O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:43])[CH3:21])[C:12]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2O)cc1
Solvent: c1ccccc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
To a refluxing solution of 4.3 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in 50 ml of benzene, a solution of 4.55 g of benzyloxycarbonyl chloride in 10 ml of benzene is added dropwise for 15 minutes. The mixture is refluxed for one hour, and said mixture is evaporated under reduced pressure to remove solvent. 30 ml of ethanol and 50 ml of an aqueous sodium hydroxide solution are added to the residue, and the mixture is stirred at room temperature for 2 hours. Then, the mixture is diluted with water, and the aqueous mixture is extracted with chloroform. The extract is washed with water, dried and evaporated to remove solvent. 4.79 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]([F:23])([F:22])[C:13]1[NH:21][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=1.Cl[C:25]([O:27][CH3:28])=[O:26].O>C1COCC1.ClCCl>[F:23][C:12]([F:11])([F:22])[C:13]1[N:21]([C:25]([O:27][CH3:28])=[O:26])[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=1
Reactant: COC(=O)Cl
Reactant: FC(F)(F)c1cc2cccnc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)n1c(C(F)(F)F)cc2cccnc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 60.6 %

Procedure:
Lithium hexamethyldisilazide (3.6 mL, 3.6 mmol, 1M in THF) was added to a solution of 2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (0.57 g, 3.04 mmol; see WO 2008/034860) in THF (20 mL) at −78° C. The reaction mixture was stirred at −78° C. for 5 minutes, then warmed up to 0° C. for 30 minutes, and finally warmed to room temperature for another 30 minutes. The mixture was cooled back to −78° C. where methyl chloroformate (0.35 mL, 4.55 mmol) was added dropwise. The mixture was slowly warmed up to room temperature and stirred for 16 hours. Water was then added, followed by dichloromethane. The layers were separated. The aqueous layer was extracted twice with dichloromethane. The organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography to afford methyl 2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.45 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH2:13]([O:20][C:21](=[O:27])[NH:22][CH:23]([CH3:26])[CH2:24]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[CH2:13]([O:20][C:21](=[O:27])[NH:22][CH:23]([CH3:24])[CH2:26][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[C:2]([Cl:1])=[N:3]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(CBr)NC(=O)OCc1ccccc1
Reactant: COc1ccc2c(Cl)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Cl)nn(CC(C)NC(=O)OCc3ccccc3)c2c1
Reaction time: 18 h
Yield: 72.2 %

Procedure:
To a solution of the product from Step C (0.18 g, 1 mmol) and (2-bromo-1 methyl-ethyl)-carbamic acid benzyl ester (0.27 g, 1 mmol) in DMF (2 mL) was added potassium carbonate (0.17 g, 1.2 mmol) and the mixture stirred at 75° for 18 h. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture and the aqueous layer was separated and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (30 mL), dried (MgSO4), and evaporated to a residue that was purified by chromatography (silica, hexane to 15% ethyl acetate in hexane) to give a syrup (0.27 g): APCl/LCMS m/z 374 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(F)cc1)C(=O)c1cccs1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1-c1cccs1
Yield: 74.8 %

Procedure:
38.6 g of ethyl 3-(4-fluorobenzoylamino)-3-(2-thienylcarbonyl)propionate, 100 ml of dimethylformamide and 20.3 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 27.4 g of ethyl 2-[2-(4-fluorophenyl)-5-(2-thienyl)-4-oxazolyl]acetate are thereby obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH:6]=[C:5]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1.[CH:21]([C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1)=[CH2:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:8]1([CH3:13])[CH2:7][CH:6]=[C:5]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]2[C:3](/[CH:22]=[CH:21]/[C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=3)=[CH:2][CH:11]=[CH:10][C:9]1=2
Reactant: C=Cc1ccc(C(=O)OCC)cc1
Reactant: CC1(C)CC=C(Sc2ccccc2)c2cc(Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(/C=C/c2cccc3c2C(Sc2ccccc2)=CCC3(C)C)cc1
Temperature: 90 °C

Procedure:
To a degassed solution of 0.35 g (1.0 mmol) of 2-bromo-5,6-dihydro-5,5-dimethyl-8-(phenylthio)-naphthalene (Compound A35) and 0.34 g (1.9 mmol) of ethyl 4-vinylbenzoate in 4.0 mL of triethylamine, was added 0.066 g (0.2 mmol) of tri-o-tolylphosphine and then 0.025 g (0.1 mmol) of palladium(II) acetate. The reaction was heated at 90° C. for 2.25 h. The reaction was concentrated in vacuo. The residue was purified by flash chromatography (silica, 5% ethyl acetate in hexane), followed by recrystallization using EtOH to afford the title compound as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:34])[CH2:16][C:17](=[O:33])[N:18]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>C1C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:34])[CH2:16][C:17](=[O:33])[N:18]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:28][CH:27]=1)[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH3:13]
Reactant: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1ccc(N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Yield: 94.2 %

Procedure:
A solution of benzyloxycarbonyl chloride (539 mg) in benzene (1.5 ml) is added dropwise to a mixture of ethyl[N-(p-aminobenzyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (810 mg), potassium carbonate (595 mg), benzene (10 ml) and water (10 ml) at a temperature of 8° C. under stirring. The mixture is stirred at the same temperature for 30 minutes. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried and then distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent, ethyl acetate:benzene=3:7) to give ethyl[N-(p-(N-benzyloxycarbonylamino)benzyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (1.08 g, 94.2%) as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[OH-].[Na+].[CH2:18](Br)[C:19]#[CH:20]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>[CH2:20]([O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)[C:19]#[CH:18]
Reactant: Oc1ccc2cc3ccccc3cc2c1
Reactant: C#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCOc1ccc2cc3ccccc3cc2c1
Reaction time: 8 h
Yield: 43.6 %

Procedure:
Into a reaction flask fitted with a stirrer, a thermometer, a nitrogen gas inlet tube and a reflux condenser, were placed 26.677 parts of 2-hydroxyanthracene, 49.444 parts of deionized water, 6.217 parts of NaOH and 0.096 part of tetrabutylammonium bromide and to this mixture, 18.859 parts of propargyl bromide was added dropwise and reacted at 80° C. for 6 hours. After completion of the reaction, the content was treated with a mixture of ethyl acetate and deionized water and the ethyl acetate layer was separated, added with magnesium sulfate and kept standing overnight to effect dehydration. After filtering off magnesium sulfate, the solvent was removed off by an evaporator and the residue was subjected to a column chromatography (silica gel 200 mesh) to obtain a purified 2propargyloxyanthracene. Yield 43.6%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([B:9]2[O:16][C:15](=[O:17])[CH2:14][N:13]([CH3:18])[CH2:12][C:11](=[O:19])[O:10]2)[C:5]([F:8])=[N:6][CH:7]=1.[Cl-].[C:21]([O:25][C:26](=[O:29])[CH2:27][Zn+])([CH3:24])([CH3:23])[CH3:22].CCOCC>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O1CCOCC1>[F:8][C:5]1[N:6]=[CH:7][C:2]([CH2:27][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:29])=[CH:3][C:4]=1[B:9]1[O:16][C:15](=[O:17])[CH2:14][N:13]([CH3:18])[CH2:12][C:11](=[O:19])[O:10]1
Reactant: CN1CC(=O)OB(c2cc(Br)cnc2F)OC(=O)C1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN1CC(=O)OB(c2cc(CC(=O)OC(C)(C)C)cnc2F)OC(=O)C1
Temperature: 80 °C
Yield: 62 %

Procedure:
To 2-(5-bromo-2-fluoropyridin-3-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (2.79 g, 8.43 mmol) was added dioxane (84 mL), bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.299 g, 0.422 mmol) and (2-tert-butoxy-2-oxoethyl)zinc(II) chloride in ether (25.3 mL, 12.65 mmol) (Rieke Metals), and the resulting mixture was sparged with nitrogen for 5 min at ambient temperature. The reaction mixture was then heated to 80° C. for 2 h. The reaction mixture was subsequently cooled to ambient temperature, adsorbed onto silica gel, and purified via flash chromatography (silica gel) with 100% DCM to 5% MeOH/DCM to give the title compound (62% yield) as a beige solid. m/z (ESI, +ve ion) 367.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=[O:9])=[C:6]([OH:12])[C:5]([Br:13])=[CH:4][CH:3]=1.O.[OH-].[Li+].O>O1CCOCC1>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([OH:12])[C:5]([Br:13])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(N)ccc(Br)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(Br)c(O)c1C(=O)O
Temperature: 100 °C
Yield: 121.9 %

Procedure:
A mixture of methyl 6-amino-3-bromo-2-hydroxybenzoate (prepared according to Wang et al, Bioorg Med Chem Lett 2007 17 2817, 5.41 g) and lithium hydroxide monohydrate (9.23 g) was suspended in dioxane (100 mL) and water (100 mL) and heated at 80° C. overnight. The temperature was then increased to 100° C. for 4 hours. A further amount of lithium hydroxide monohydrate (4.61 g) was added and the reaction mixture was heated at 100° C. for a further 1 hour. After cooling, the mixture was concentrated in vacuo and the residue was acidified to pH3 with formic acid and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and the filtrate was concentrated in vacuo to give 6-amino-3-bromo-2-hydroxybenzoic acid (6.22 g) as a black/grey solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[N:3]=1.[N:22]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][C:2]1[C:6]([C:7]([N:30]2[CH2:31][CH2:32][CH:27]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:28][CH2:29]2)=[O:8])=[C:5]([CH3:10])[N:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:12]=2)[N:3]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1ccc(-n2nc(C)c(C(=O)O)c2C)cc1C(F)(F)F
Product: Cc1ccc(-n2nc(C)c(C(=O)N3CCC(N4CCCC4)CC3)c2C)cc1C(F)(F)F
Yield: 77 %

Procedure:
In analogy to the procedure described in Example 18], 3,5-dimethyl-1-(4-methyl-3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 77% yield as orange foam. MS: 435.5 (MH+).
Reaction SMILES: Cl.[CH2:2]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=O)=[CH:11][CH:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(OC(=O)C(=COCC)C(OCC)=O)C.CC[O-].[Na+].C(O[C:40]([C:42]1[C:43](O)=[N:44]C(C2C=CC(CCCCCCC)=CC=2)=[N:46][CH:47]=1)=O)C.P(Cl)(Cl)(Cl)=O.C(OC(C1C(Cl)=NC(C2C=CC(CCCCCCC)=CC=2)=NC=1)=O)C>C(O)C>[C:47]([C:42]1[CH:40]=[N:15][C:13]([C:12]2[CH:16]=[CH:17][C:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=2)=[N:44][CH:43]=1)#[N:46]
Reactant: CCCCCCCc1ccc(-c2ncc(C(=O)OCC)c(O)n2)cc1
Reactant: CCCCCCCc1ccc(C(N)=O)cc1
Agent: CCCCCCCc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 366 from p-n-heptylbenzamide hydrochloride [prepared according to H. Schubert and H. Zaschke, J. prakt. Chem. 312, 494 (1970) from p-n-heptylbenzonitrile; melting point 126.0°-127.3° C] and ethoxymethylenemalonic acid diethyl ester with sodium ethylate in ethanol and subsequent treatment of the obtained 2-(p-n-heptylphenyl)-4-hydroxy-5-pyrimidinecarboxylic acid ethyl ester (melting point 184.7°-185.3° C) with phosphorus oxychloride. The melting point of 2-(p-n-heptylphenyl)-4-chloro-5-pyrimidinecarboxylic acid ethyl ester is 49.2°-49.8° C.
Reaction SMILES: N[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C([N:15](CC)CC)C.C(S(Cl)=O)(C)(C)C>ClCCl>[NH2:15][CH:6]1[CH2:7][CH2:2][CH2:3][CH2:4][N:5]1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CCN(CC)CC
Agent: CC(C)(C)S(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCCCC1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 126 %

Procedure:
Ethyl 4-amino-1-piperidinecarboxylate (300 mg) and triethylamine (258 mg) were dissolved in 5 ml of dichloromethane. To the mixture, 2 ml of solution of t-butylsulfinyl chloride (222 mg) in dichloromethane was added and the mixture was stirred at room temperature for 4 hours. The solution was partitioned into an aqueous solution of potassium hydrogen sulfate and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography to give 378 mg of 4-t-butylsulfiny amino-1-ethoxycarbonyl piperidine.
Reaction SMILES: N[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]([CH3:13])[CH3:12])=[CH:8][CH:9]=2)[S:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].N(OCCC(C)C)=O>O1CCCC1>[CH:11]([C:7]1[N:6]=[C:5]2[S:4][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2][C:10]2=[CH:9][CH:8]=1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1sc2nc(C(C)C)ccc2c1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C(C)C)nc2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
3-Cyano-6-isopropyl-2-mercaptopyridine (50 g) synthesized according to U.S. Pat. No. 5,001,137 (Mar. 19, 1991), sodium ethoxide (22.9 g) and bromoethyl acetate (34.2 ml) were added to ethanol (500 ml) and the mixture was stirred at room temperature for 1 hr and the solvent was evaporated. The residue was recrystallized from ethanol to give ethyl 3-amino-6-isopropylthieno[2,3-b]pyridine-2-carboxylate (69.3 g) (melting point: 161-162° C.). (2) This ester (30 g) and isoamyl nitrite (45.7 ml) were added to tetrahydrofuran (300 ml) and the mixture was stirred at 60° C. for 2 hr and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase; chloroform) to give ethyl 6-isopropylthieno[2,3-b]pyridine-2-carboxylate (7.1 g). melting point: 73-74° C. (3) This was subjected to hydrolysis under basic conditions according to a conventional method to give the title compound (5.8 g). melting point: 218-220° C.