Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:7]([F:10])([F:9])[CH3:8])[C:3]([F:6])([F:5])[F:4].S(=O)(=O)(O)[OH:12]>O>[CH3:1][C:2]([OH:12])([C:7]([F:10])([F:9])[CH3:8])[C:3]([F:6])([F:5])[F:4]
Reactant: O=S(=O)(O)O
Reactant: CC(C(C)(F)F)C(F)(F)F
Solvent: O
Product: CC(F)(F)C(C)(O)C(F)(F)F

Procedure:
As another example, 2-methyl-1,1,1,3,3-pentafluoro-2-butanol may be prepared by fluorinating commercially available 2-methyl-1-buten-3-yne to form 2-methyl-1,2,3,4-tetrafluoro-1-butene which may then be reacted with hydrogen fluoride to form 2-methyl-1,2,3,3,4-pentafluorobutane. The 2-methyl-1,2,3,3,4-pentafluorobutane may then be dehalogenated to form 3-methyl-2,3,4-trifluoro-1-butene which may then be reacted with hydrogen fluoride to form 2-methyl-1,2,3,3-tetrafluorobutane. The 2-methyl-1,2,3,3-tetrafluorobutane may then be dehalogenated to form 2-methyl-1,3,3-trifluoro-1-butene which may then be fluorinated to form 2-methyl-1,1,2,3,3-pentafluorobutane. The 2-methyl-1,1,2,3,3-pentafluorobutane may then be dehydrohalogenated to form 2-methyl-1,1,3,3-tetrafluoro-1-butene which may then be reacted with hydrogen fluoride to form 2-methyl-1,1,1,3,3-pentafluorobutane. The 2-methyl-1,1,1,3,3-pentafluorobutane may then be dehydrogenated and then reacted with sulfuric acid and water to form 2-methyl-1,1,1,3,3-pentafluoro-2-butanol.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[O:11]=[C:12]1[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][N:13]1[C:20]([O-:22])=[O:21].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:23]([CH:16]1[CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][N:13]([C:20]([O:22][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:21])[C:12]1=[O:11])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CCCC1CC(=O)N(C(=O)[O-])C1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC1CN(C(=O)OC(C)(C)C)C(=O)C1Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 1.0 M tetrahydrofuran solution of lithium hexamethyldisilazane (6.2 ml, 6.2 mmol) was gradually added to a solution of tert-butyl. 2-oxo-4-propyl-1-pyrrolidinecarboxylate (1.35 g, 5.94 mmol) in tetrahydrofuran (20 ml) at −70° C. and the mixture was stirred for 15 minutes. Benzyl bromide was added to the reaction mixture and the temperature of the mixture was gradually raised to 0° C. and it was stirred for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (1.22 g) as a light yellow oil. 1H-NMR (CDCl3) δ(ppm) 0.80 (3H, t, J=7.2 Hz), 1.10-1.40 (4H, m), 1.52 (9H, s), 1.87-1.95 (1H, m), 2.44-2.52 (1H, m), 2.90 (1H, dd, J=14.4 Hz, 7.2 Hz), 3.10 (1H, dd, J=14.4 Hz, 5.2 Hz), 3.15 (1H, dd, J=10.8 Hz, 8.0 Hz), 3.71 (1H, dd, J=10.8 Hz, 8.0 Hz), 7.15-7.33 (5H, m)
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13]([CH2:23][NH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>N1C=CC=CC=1>[C:35]([N:24]([CH2:23][C:13]1[C:12](=[O:33])[C:11]2[C:16](=[CH:17][C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:9]([F:34])[CH:10]=2)[N:15]([CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[CH:14]=1)[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:37])[CH3:36]
Reactant: CCOC(=O)CCCNCc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CCCN(Cc1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
170 mg of ethyl 4-({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}amino)butanoate was dissolved in 2.0 ml of pyridine, and 0.040 ml of acetic anhydride was added, followed by overnight stirring at room temperature. After concentrating the reaction mixture under a reduced pressure, water was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then filtered and concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 165 mg of ethyl 4-(acetyl {[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}amino)butanoate was obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)[CH3:2]
Reactant: CCOC(CN)OCC
Reactant: BrCc1ccc2ccccc2c1
Product: CCOC(CNCc1ccc2ccccc2c1)OCC
Yield: 77.6 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2,2-diethoxyethanamine (5.82 ml, 40 mmol) was reacted with 2-(bromomethyl)naphthalene (4.42 g, 20 mmol) and the obtained residue was purified by Büch silica gel column chromatography (eluent: n-hexane:ethyl acetate=90:10 to 80:20) to obtain the title compound (4.24 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:28][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)NC1CCCCC1
Yield: 57 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using cyclohexylamine (24 μL, 0.21 mmol) as the coupling partner. Concentration (no chromatography) yielded 36 mg (57%) of the titled compound. ESI-MS m/z 373 (MH+), 371 (M−H−).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C.C(O)C.O>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(OCCCN2CCCCC2)cc1
Temperature: 28 °C
Reaction time: 8 h

Procedure:
To methyl 4-(3-piperidin-1-ylpropoxy)benzoate ax15 (4.41 g, 15.9 mmol, 1 eq) in ethanol (160 ml) is added a 5 N aqueous solution of sodium hydroxide (9.54 ml, 47.7 mmol, 3 eq) and the mixture is stirred at 60° C. for 4 h and at 28° C. overnight. The mixture is concentrated under vacuum to give a white solid, which is then dissolved in a 1:1 mixture of ethanol/water (100 ml). A solution of 5 N aqueous hydrochloric acid is then added until the pH of the mixture reaches 2-3. The ethanol is then evaporated under vacuum and the mixture filtered to give a white solid. This solid is washed with water and dried under vacuum at 40° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([SH:21])[N:3]=1.Br[CH2:23][CH2:24][OH:25].C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:18]=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4]([S:21][CH2:23][CH2:24][OH:25])[N:3]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc2c(c1)OCO2
Reactant: OCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCCO)c(C#N)c1-c1ccc2c(c1)OCO2

Procedure:
75 mg (0.19 mmol) of 2-amino-4-(1,3-benzodioxol-5-yl)-6-sulfanyl-3,5-pyridinedicarbonitrile [prepared analogously to Dyachenko et al., Russian Journal of Chemistry 33 (7), 1014–1017 (1997); 34 (4), 557–563 (1998)] and 47 mg (0.38 mmol) of 2-bromoethanol and 63 mg (0.75 mmol) of sodium bicarbonate are stirred in 1 ml of DMF at room temperature overnight. Water is then added, and the precipitated product is filtered off with suction and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:19])[CH2:12][CH:13]([CH3:18])[CH2:14][C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH2:34][CH3:35])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=3.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:19])[CH2:12][CH:13]([CH3:18])[CH2:14][C:15]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[N:25]([CH2:34][CH3:35])[C:26]4[C:31]([C:32]=3[CH:33]=2)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:17])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)Nc3ccc(C#N)c(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.5 %

Procedure:
To a solution of the compound obtained in Step 1 (300 mg, 1.07 mmol), 3-amino-9-ethylcarbazole (270 mg, 1.28 mmol) and DIEA (0.560 mL, 3.21 mmol) in DMF (6 mL) was added HATU (610 mg, 1.60 mmol), and the mixture was stirred at room temperature for 14 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane) to give the title compound (225 mg, 0.476 mmol, 44.5%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[CH3:12][CH:13](O)[CH3:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:1][C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:13]([CH3:14])[CH3:12]
Reactant: CC(C)O
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)n1cnc2c(Cl)nc(F)nc21
Reaction time: 8 h
Yield: 63.8 %

Procedure:
6-Chloro-2-fluoro-9H-purine (517.7 mg, 3 mmol), 2-propanol (198.3 mg, 3.3 mmol), PPh3 (866 mg, 3.3 mmol) was mixed under N2 in a 50 mL round-bottom flask at 0° C. DEAD (575 mg, 3.3 mmol) was added via syringe dropwise to the mixture. The temperature was raised to r. t. and the mixture was stirred overnight. Sovent was removed in vacuo and the resulting residue was chromatographed on silica gel (CH2Cl2/EtOAc, 4:1, Rf 0.62). The product was obtained as a white solid (411 mg, 64%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH3:22]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:21][CH3:22])[CH2:30][CH2:31]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: CCc1ccccc1N1CCNCC1
Reactant: COc1nc(C)c(C)nc1NC(=S)Oc1ccccc1
Product: CCc1ccccc1N1CCN(C(=S)Nc2nc(C)c(C)nc2OC)CC1
Yield: 64 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[CH2:32][C:33](O)=[O:34]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:33](=[O:34])[CH2:32][C:26]3[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)Cc1c(Cl)cccc1Cl

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and (2,6-dichloro-phenyl)-acetic acid to yield (3aR,4S,7aR)-4-[2-(2,6-dichloro-phenyl)-acetoxy]-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=9.620 min; HPLC Method I
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH2:21][CH3:22])=[C:15](B(O)O)[CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(C)=O.C(COC)OC>[Cl:8][C:6]1[CH:7]=[C:2]([C:13]2[CH:12]=[C:11]([Cl:10])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH3:22])[N:3]=[C:4]([NH2:9])[N:5]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CCOc1ccc(Cl)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CC(C)=O
Solvent: O
Product: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73.3 %

Procedure:
To a mixture of 4,6-dichloro-pyrimidin-2-ylamine (0.50 g, 3.0 mmol), 5-chloro-2-ethoxy-phenyl boronic acid (0.61 g, 3.0 mmol), palladium (II) acetate (0.10 g, 0.46 mmol), and triphenylphosphine (0.24 g, 0.91 mmol) was added a solution of sodium carbonate (1.6 g, 15.2 mmol) in water (5 ml) followed by glyme (20 ml). The mixture was stirred under an argon atmosphere at room temperature for 3.5 hours. Acetone (20 ml) was added and the mixture was filtered through a pad of celite under suction. The filtrated was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 15% ethyl acetate-hexane followed by 20% ethyl acetate-hexane to provide 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine (0.625 g, 73% yield) as a white powder.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][Si:24]([CH3:53])([CH3:52])[C:25]1[CH:26]=[C:27]([CH:45]=[C:46]([Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:47]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34](/[C:37](/[CH3:44])=[CH:38]/[C:39]([O:41]CC)=[O:40])=[CH:33][CH:32]=1)=O>C1(C)C=CC=CC=1>[CH3:23][Si:24]([CH3:53])([CH3:52])[C:25]1[CH:26]=[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34](/[C:37](/[CH3:44])=[CH:38]/[C:39]([OH:41])=[O:40])=[CH:33][CH:32]=2)=[S:10])[CH:45]=[C:46]([Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:47]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C/C(=C\C(=O)O)c1ccc(NC(=S)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Yield: 168.1 %

Procedure:
Lawesson's reagent (134 mg) was added to a toluene (5 ml) solution of Compound 19c (300 mg), and the obtained mixture was stirred while refluxing under heating for 20 minutes. After the mixture was allowed to cool, the solvent was distilled off. The obtained residue was purified by column chromatography (6.25% ethyl acetate/n-hexane). Fractions containing the ester body of Compound 19 were collected and concentrated to dryness. As a result, 246 mg of yellow solid was obtained. The obtained yellow solid was, without further purification, dissolved in ethanol (10 ml), and a 2N sodium hydroxide aqueous solution (2.62 ml) was added thereto in a nitrogen atmosphere. The obtained mixture was stirred under heating at 70° C. for 2 hours. After the reaction was over, the mixture was allowed to cool. A 2N hydrochloric acid aqueous solution was added thereto, and the mixture was separated with ethyl acetate and water. The organic layer was washed once with water and once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and as a result, Compound 19 (112 mg, 48%) was obtained as a yellow solid.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@@H:18]([CH3:42])[C:19](=[O:41])[NH:20][C@@H:21]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[C:22](=[O:32])[NH:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:17][C@@H:18]([CH3:42])[C:19]([NH:20][C@@H:21]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[C:22]([NH:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:32])=[O:41]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: C[C@H](N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of material from Example 99 (577 mg, 0.579 mmol) in anhydrous DMF (4 mL) is added piperidine (1 mL, 10.1 mmol). The resulting solution is stirred at room temp for 20 min, then the solvent is removed in vacuo. The resulting solid is evaporated sequentially from ethyl acetate, 1,2-dichloroethane and dichloromethane and dried under high vacuum for several hours to give the title compound as a white solid in quantitative yield that contains 1 equivalent of 1-((9H-fluoren-9-yl)methyl)piperidine as a side product. LC/MS (Condition A): ret. T=4.05 min, (M+H)+ 366.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:22]([O-:24])=[O:23])=[C:12]([CH:21]=1)[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:22]([O-:24])=[O:23])=[C:12]([CH:21]=1)[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: O=[N+]([O-])c1ccc(F)cc1Oc1ccccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccccc1Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
Methyl bromoacetate (36.33 g, 0.24 mol) is added to a mixture of o-(5-fluoro-2-nitrophenoxy)phenol (39.45 g, 0.16 mol) and potassium carbonate (32.75 g, 0.24 mol) in N,N-dimethylformamide. The reaction mixture is stirred at room temperature for 18 hours, poured into water and extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a yellow solid (42 g) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)C(C)C)(C)C.Br[C:26]1[S:30][C:29]([C:31]#[N:32])=[N:28][N:27]=1.[NH4+].[Cl-]>O1CCOCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:26]2[S:30][C:29]([C:31]#[N:32])=[N:28][N:27]=2)[CH2:9][CH2:10]1
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Reactant: N#Cc1nnc(Br)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1nnc(N2CCC(Oc3cc(F)ccc3Br)CC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-bromo-5-fluorophenoxy)piperidine (15.16 g, 52.5 mmol) in 1,4-dioxane (80 mL) was added N,N-diisopropylethylamine (Hünig's base or DIPEA) (20 mL, 115 mmol) followed by 5-bromo-1,3,4-thiadiazole-2-carbonitrile (10.02 g, 52.7 mmol). The mixture was stirred 1 h at room temperature. The reaction mixture was then poured into saturated aqueous NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (eluting with 10-40% EtOAc/hexanes) to afford the desired product as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([CH3:16])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Mg]Cl>C1COCC1.C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni]>[C:2]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH3:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1[Mg]Cl
Reactant: Clc1ccccc1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Solvent: C1=CCCC=CCC1
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccc1
Reaction time: 15 h
Yield: 96.3 %

Procedure:
The general procedure from Example 13 was followed using chlorobenzene (1.126 g, 10.0 mmol) and o-tolylmagnesium chloride (15 mL, 15.0 mmol) with Ni(COD)2 (83.4 mg, 0.303 mmol) and (Me3C)2PH(O) (50.0 mg, 0.303 mmol) in 20.0 mL of THF. After 15 h at room temperature, the reaction mixture was quenched with 10 mL of H2O. The mixture above was extracted with 3×50 mL of diethyl ether. The combined ether extracts were dried over mgSO4, filtered, and the ether and THF removed from the filtrate by rotary evaporation. The resulting residues were chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 1.62 g (96% yield) of 2-phenyltoluene. It was >95% pure by 1H NMR. 1H NMR (500 MHz, CDCl3): δ7.62-7.47 (m, 9H), 2.50 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ142.0, 141.9, 135.2, 130.3, 129.7, 129.1, 128.0, 127.2, 126.7, 125.7, 20.4. ppm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:19](OCC)=[O:20])[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]3[O:16][CH:17]=[CH:18][C:12]=3[C:11]=12.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:7]1([CH2:19][OH:20])[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]3[O:16][CH:17]=[CH:18][C:12]=3[C:11]=12
Reactant: CCOC(=O)c1cnn2ccc3occc3c12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cnn2ccc3occc3c12
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
To a suspension of 80% lithium aluminum hydride (250 mg, 5.40 mmol) in tetrahydrofuran (10 mL) was added a solution of ethyl furo[3,2-c]pyrazolo[1,5-a]pyridine-1-carboxylate (310 mg, 1.35 mmol) in tetrahydrofuran (10 mL) at room temperature, and the mixture was stirred at 50° C. for 5 min. Sodium sulfate decahydrate (4.3 g) was added under ice-cooling, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) and further washed with diisopropyl ether to give the title compound (125 mg, yield 49%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12.[IH:11]>>[I:11][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12
Reactant: Clc1ccnc2[nH]cnc12
Reactant: I
Product: Ic1ccnc2[nH]cnc12

Procedure:
A mixture of 7-chloro-3H-imidazo[4,5-b]pyridine (1.47 g, 9.64 mmol) and 15 mL of 57% hydriodic acid were reacted at 80° C. for 4 h. After the solid was filtered off it was resubmitted to the reaction with 10 mL of fresh 57% hydriodic acid. The reaction yielded 1.3 g of the product as a black powder, 90% pure.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH2:18][CH3:19]>CN(C=O)C>[CH2:17]([N:3]1[C:4](=[O:10])[C:5]2[CH:9]=[CH:8][NH:7][C:6]=2[N:1]=[CH:2]1)[CH2:18][CH3:19]
Reactant: CCCI
Reactant: O=c1[nH]cnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnc2[nH]ccc2c1=O
Temperature: 55 °C
Reaction time: 20 h

Procedure:
Under argon gas, 7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.0 g) was dissolved in DMF (35 ml) with warming. Then, anhydrous potassium carbonate (1.02 g) and propyl iodide (1.08 ml) were added and the mixture was stirred at 55° C. for 20 hours. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (silica gel; hexane: ethyl acetate=4:1-1:1) to provide the title compound (521 mg). 1H-NMR (CDCl3) 8: 0.96(3H,t,J=7.4Hz), 1.73-1.92(2H,m), 4.01(2H,t,J=7.4Hz), 6.71(1H,dd,J=2.2&3.4Hz), 7.01(1H,dd,J=2.2&3.4Hz), 7.94(1H,s).