Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10]([O-])(=[O:12])=[O:11])[CH3:2].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:17]>>[Cl:17][S:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])(=[O:12])=[O:11]
Reactant: CCOC(=O)CCCCCS(=O)(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Product: CCOC(=O)CCCCCS(=O)(=O)Cl
Yield: 61 %

Procedure:
Sodium 6-ethoxy-6-oxo-1-hexanesulfonate (62b) (1.68 g, 6.8 mmol) was mixed with phosphorus pentachloride and the mixture was carefully pestled in a mortar. After the reaction came to the end (the foaming of the reaction mixture ceased) the mixture was extracted with dry benzene (50 ml). The extract was evaporated under reduced pressure and the residue was dried in vacuum to give crude title compound (1.03 g, 61%) as a hygroscopic oil. The chloride (63b) was used in further reactions without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:19]=2)[N:14]=1>O>[O:23]([C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:9]([C:6]3[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:11])=[N:14]2)=[CH:19][CH:18]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(C(=O)O)nn1
Reactant: Nc1ccc2ccc(Oc3ccccc3)nc2n1
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccccc4)nc3n2)nn1
Yield: 70.6 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 6-methoxy-3-pyridazinecarboxylic acid (2.2 g), N,N'-carbonyldiimidazole (2.3 g) and 2-amino-7-phenoxy-1,8-naphthyridine (2.7 g). The product obtained by precipitation in water is purified by recrystallization in acetonitrile (300 cc). N-(7-Phenoxy-1,8-naphthyridin-2-yl)-6-methoxy-3-pyridazinecarboxamide (3 g), m.p. 95° C., is thereby obtained.
Reaction SMILES: C1COCC1.[CH:6]1([C:9]2[C:10]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:11][C:12]([O:19][CH:20]([CH3:22])[CH3:21])=[C:13]([CH:18]=2)[C:14](OC)=[O:15])[CH2:8][CH2:7]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH:6]1([C:9]2[C:10]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:11][C:12]([O:19][CH:20]([CH3:22])[CH3:21])=[C:13]([CH:18]=2)[CH:14]=[O:15])[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2)nc1OC(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1nc(-c2ccc(F)cc2)c(C2CC2)cc1C=O
Reaction time: 0.08 h
Yield: 85 %

Procedure:
A THF (20 mL) solution of methyl 5-cyclopropyl-6-(4-fluorophenyl)-2-isopropoxynicotinate (3.17 g) was added to a THF (20 mL) suspension of lithium aluminum hydride (365 mg) under ice cooling in a nitrogen atmosphere. After stirring at the same temperature as above for 30 minutes, water (0.35 mL) and a 15% aqueous sodium hydroxide solution (0.35 mL) were added thereto, and the mixture was stirred for 5 minutes. Then, water (1.05 mL) was further added thereto. The reaction mixture was stirred for 30 minutes and then filtered. The filtrate was concentrated under reduced pressure. Manganese dioxide (8.36 g) was added to a toluene (30 mL) solution of the obtained residue, and the mixture was stirred at 60 C for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.45 g)
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CN(C=O)C.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>O>[O:20]=[C:18]1[N:17]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:16](=[O:21])[CH:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]3)=[CH:23][CH:22]=2)[S:19]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Sodium hydride (60% in mineral oil, 66 mg, 1.65 mmol) was added into a mixture of 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (500 mg, 1.65 mmol) (which was obtained in Example 38), and DMF. The mixture was stirred for 1 hour at room temperature, and then tert-butyl bromoacetate (0.36 mL, 2.47 mmol) was added. The new mixture was stirred for 30 minutes, poured into water, and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate 3/1) gave a viscous oil (525 mg, 76% yield); 1H NMR (300 MHz, DMSO-d6) δ 1.40 (s, 9 H), 2.40 (m, 4H), 2.9 (m, 1H), 3.45 (m, 1H), 3.56 (m, 4H), 4.20 (s, 2H), 5.05 (m, 1H), 6.97 (m, 2H), 7.18 (m, 2H); MS (ES) m/z: 419 (MH+); Anal. Calcd. for C15H16N2O3S: C, 60.27; H, 6.26; N, 6.69. Found: C, 60.21; H, 6.44; N, 6.52.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.[O:18]=[S:19]1(=[O:36])[CH2:24][CH2:23][N:22]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[C:21]2=[N:20]1>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:35][C:32]2[CH:31]=[CH:30][C:29]([C@H:28]3[C:21]4=[N:20][S:19](=[O:36])(=[O:18])[CH2:24][CH2:23][N:22]4[CH2:25][CH2:26][CH2:27]3)=[CH:34][CH:33]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4ccc(Cl)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15.9 %

Procedure:
Diacetoxycopper (1037 mg) was added to a mixture of triethylamine (1.983 mL), 4-chlorophenylboronic acid (1339 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (800 mg) and in DMF (dry) (30 ml). The mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube for 15 hr. Then 4-chlorophenylboronic acid (1339 mg) and diacetoxycopper (1037 mg) were added and the mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube for 2 days. The insoluble material was removed by filtration, and the filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with 0.1N NaOH aq., dried over anhydrous magnesium sulfate. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then crystallized from THF/IPE to give the title compound (177 mg) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[C:15][Si](C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CO.C(Cl)Cl.C(Cl)Cl>[C:14]([C:10]1[CH:9]=[C:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=1)#[CH:15]
Reactant: C[Si](C)(C)C#Cc1cccc(-c2cccnc2F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cccc(-c2cccnc2F)c1
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 2-fluoro-3-{3-[(trimethylsilyl)ethynyl]phenyl}pyridine (2.20 g, 8.1 mmol) in MeOH/CH2Cl2 (1/1, 60 mL) is added Cs2CO3 (3.17 g, 9.7 mmol) at room temperature. After stirring for 1 h, the reaction mixture is diluted with CH2Cl2 and passed through a thin layer of silica gel. The solution is concentrated and the crude material is purified by chromatography (silica gel, EtOAc/hexane:20/80) to give the title compound (1.23 g, 77%) as a solid. mp: 45-47° C. MS (+) EI: 198 M+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]2)[S:5][CH:6]=1.[CH3:17][C:18]1([CH3:37])[C:27]2[CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=[CH:23][C:22]=2[CH2:21][CH2:20][CH2:19]1.Cl>>[CH3:17][C:18]1([CH3:37])[C:27]2[CH:26]=[C:25]([C:2]3[N:3]=[C:4]([N:7]4[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]4)[S:5][CH:6]=3)[CH:24]=[CH:23][C:22]=2[CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)CCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: OCCNC1CCN(c2nc(Br)cs2)CC1
Agent: Cl
Product: CC1(C)CCCc2ccc(-c3csc(N4CCC(NCCO)CC4)n3)cc21

Procedure:
The preparation is carried out as described above starting from 100 mg (0.27 mmol) of 2-[1-(4-bromothiazol-2-yl)piperidin-4-ylamino]ethanol and 98 mg (0.30 mmol) of 2-(8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The product is in the form of the hydrochloride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=O)[CH2:17][CH3:18])=[CH:15][C:10]=2[N:9]=[CH:8]1.Cl.[NH2:21][OH:22].CC([O-])=O.[Na+]>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=[N:21][OH:22])[CH2:17][CH3:18])=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: CCC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCC(=NO)c1ccc2c(c1)ncn2C1CCCCO1
Yield: 89.1 %

Procedure:
To a solution of 170 (100 mg, 0.39 mmol) in MeOH (5 mL) was added hydroxylamine hydrochloride (54 mg, 0.78 mmol) and NaOAc (100 mg, 1 mmol). The mixture was refluxed overnight. The mixture was extracted with EtOAc, washed sequentially with H2O and brine and dried (Na2SO4), filtered and concentrated in vacuo to afford 95 mg (90%) of 1-[1-(tetrahydro-pyran-2-yl)-1H-benzoimidazol-5-yl]-propan-1-one oxime (172) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.P(Cl)(Cl)Cl.[NH3:22]>C1C=CC=CC=1>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH2:22])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccccc2C(=O)O)cc1
Reactant: N
Solvent: c1ccccc1
Solvent: ClP(Cl)Cl
Product: Cc1ccc(Oc2ccccc2C(N)=O)cc1

Procedure:
2-[4-Methylphenoxy]benzoic acid, prepared as described by D. J. Carini in J. Medicinal Chem., 33, 1330- (1990), is converted to the corresponding acid chloride with phosphorous trichloride in benzene. The acid chloride is reacted with ammonia to give 2-(4-methylphenoxy)-benzenecarboxamide. The carboxamide is then dehydrated by treatment with thionyl chloride to give 2-(4'-methylphenoxy)benzonitrile.
Reaction SMILES: [CH3:1][CH:2]([NH2:28])[C@H:3]1[O:8][C@H:7]([O:9][C@H:10]2[C@H:15]([OH:16])[C@H:14]([N:17]([C:19]([CH2:21][NH2:22])=[O:20])[CH3:18])[C@@H:13]([O:23]C)[C@@H:12]([OH:25])[C@@H:11]2[NH2:26])[C@H:6]([NH2:27])[CH2:5][CH2:4]1.OS(O)(=O)=O.OS(O)(=O)=O.[NH4+]>I.O>[CH3:1][CH:2]([NH2:28])[CH:3]1[O:8][CH:7]([O:9][CH:10]2[CH:15]([OH:16])[CH:14]([N:17]([C:19]([CH2:21][NH2:22])=[O:20])[CH3:18])[CH:13]([OH:23])[CH:12]([OH:25])[CH:11]2[NH2:26])[CH:6]([NH2:27])[CH2:5][CH2:4]1
Reactant: CO[C@H]1[C@@H](O)[C@H](N)[C@@H](O[C@H]2O[C@H](C(C)N)CC[C@H]2N)[C@H](O)[C@@H]1N(C)C(=O)CN
Agent: I
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: CC(N)C1CCC(N)C(OC2C(N)C(O)C(O)C(N(C)C(=O)CN)C2O)O1
Temperature: 62 °C
Reaction time: 20 h
Yield: 25 %

Procedure:
Fortimicin A sulfate (1.48 g, 2.46 mmole) was dissolved in 160 ml of 48% hydriodic acid at room temperature. The solution was stirred and the temperature gradually raised to 62° C. Stirring was continued at 62° C. for 20 hours. The solution was diluted with 160 ml of water and passed through a 1.5 l. column of "Amberlite" lRC-50 in the ammonium form. The column was washed with water and eluted with an ammonium hydroxide gradient as described in Example 1 resulting in the recovery of 3-O-demethylfortimicin A in 25% yield.
Reaction SMILES: C[CH:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:27])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:9][CH:8]=1)[C:3]([O-:5])=O.[CH3:28][O:29][CH2:30][CH2:31][NH2:32].CCOCC.[ClH:38]>ClCCl>[ClH:38].[OH:27][C@H:18]([CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17][NH:16][CH2:15][CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:2][C:3]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:5])=[CH:8][CH:9]=1
Reactant: COCCN
Reactant: CC(Oc1ccc(OCCNCC(O)COc2ccccc2)cc1)C(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COCCNC(=O)COc1ccc(OCCNC[C@H](O)COc2ccccc2)cc1

Procedure:
(-)-Methyl-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]phenoxyacetate (44.0 g) (the same starting material as in Example 2) and 2-methoxyethylamine (30 ml) were heated together on a steam-bath for 24 hours. The mixture was cooled and evaporated under reduced pressure to give an oily residue. This was dissolved in dichloromethane (200 ml) and treated with a solution of ether saturated with hydrogen chloride. The solvent was evaporated and the residual solid crystallised from a mixture of methanol and ethyl acetate to give (S)-4-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]-N-(2-methoxyethyl)phenoxyacetamide hydrochloride (39.2 g), m.p. 171°-3° C.; αS =-10.7° (c=1.0; methanol); microanalysis: found C, 58.1; H, 7.0; N, 6.0; Cl, 7.9%; required for C22H31ClN2O6 : C, 58.1; H, 6.9; N, 6.2; Cl 7.8%: NMR (DMSO-d6) 3.1(m,1H,CHCH2NH); 3.24(s,3 H,OCH3); 3.24-3.45(m,7H,CHCH2NHCH2 ; NHCH2CH2OCH3): 4.0(m,2H, ArOCH2CHOH): 4.2-4.35(m,3H,CHOH; CH2CH2OAr): 5.95(d,1H,OH); 6.85-7.05(m,7H,Ar); 7.3(m,2H,Ar); 8.15(t,1H, CONHCH2): 9.16 and 9.35 (broad peaks, 2H, NH2+).
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[CH:9]=1.C1C(=O)N([Br:56])C(=O)C1>C(#N)C>[CH3:48][Si:2]([CH3:1])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:30][CH:29]=2)[C:9]=1[Br:56]
Reactant: COC(=O)Cc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)Cc1ccc(Oc2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound, methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate (150 mg, 0.22 mmol) was dissolved in ACN (10 mL). NBS (40 mg, 0.22 mmol) was added and the mixture was stirred at room temperature for 1 h. After concentration, the product, methyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)phenyl)acetate was used in the next step without further purification. HPLC-MS tR=2.70 min (UV254 nm); mass calculated for formula C36H46BrN5O5Si2 763.2, observed LCMS m/z 764.2 (M+H).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20](Br)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO.O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)=[N:19][C:18]=3[CH3:23])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)nc3C)c(C)nc12
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccnc4)nc3C)c(C)nc12
Yield: 64.6 %

Procedure:
To a microwave pressure tube is added 0.070 g (0.178 mmol) of 8-(1-ethyl-propyl)-3-[2-bromo-4-methyl-5-thiazolyl]-2,6-dimethyl-imidazo[1,2-b]pyridazine, 0.066 g (0.534 mmol) of pyridine-3-boronic acid, 0.103 g (0.089 mmol) of Pd(PPh3)4, 0.267 mL (0.534 mmol) of 2 M aqueous Na2CO3, and 1 mL 7:3:2 DME:H2O:EtOH, and the mixture is heated at 160° C. for 60 min. The reaction mixture is partitioned between 25 mL of ethyl acetate and 25 mL of water. The layers are separated and the aqueous is extracted 3×25 mL of ethyl acetate, dried (MgSO4), and concentrated under vacuum. The crude mixture is purified by chromatography using hexanes/Ethyl acetate as a solvent system. The product containing fractions are combined to obtain 0.045 g of the product, 64% yield. MS, ES+=392.2 (M+1); 1HNMR (DMSO-d6) δ 9.18 (s, 1H); 8.65 (m, 1H); 8.34 (d, 1H); 7.60 (m, 1H); 7.06 (s, 1H); 3.06 (m, 1H); 2.50 (s, 3H); 2.40 (s, 3H); 2.34 (s, 3H); 1.87-1.82 (m, 4H); 0.83-0.79 (m, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.CN1CCOCC1.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[CH2:21]([O:28][C:29]([NH:11][CH2:10][CH2:9][C:8]1[C:12]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:13]=2)[NH:6][CH:7]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(F)cc12)OCc1ccccc1
Temperature: 0 °C
Yield: 68 %

Procedure:
To a stirred solution of 0.83 g (4-6 mmol) of 5-fluorotryptamine and 0.48 g (0.55 mL, 5 mmol) of n-methylmorpholine in 10 mL of DMF at 0° C. was added dropwise 0.72 mL (5 mmol) of benzylchloroformate. The reaction mixture was allowed to stir at 0° C. under argon. After 1.5 hours of stirring, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride, dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting residue was purified by flash chromatography using hexane:ethyl acetate (2:1) as an eluent to yield 1 g (68%) of N-(Benzyloxycarbonyl)-5-fluorotryptamine as a white solid. mp 104°-105° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1>CCOC(C)=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1ccc(C2OCCO2)nc1
Solvent: CCOC(C)=O
Product: Nc1ccc(C2OCCO2)nc1

Procedure:
2-(1,3-Dioxolanyl)-5-aminopyridine was prepared from 2-(1,3-dioxolanyl)-5-nitropyridine by the procedure employed in Example V. Yield: 2.6 g (93%); mp 81°-82° C.; TLC Rf 0.18 (EtOAc); 1H NMR (90 MHz, CDCl3) δ 3.85 (br s, 2H, 5-NH2, D2O exchangeable), 4.05 (m, 4H, CH2CH2), 5.72 (s, 1H, 2-CH), 6.95 (dd, 1H, 4-H, J3,4 =8 Hz, J4,6 =2 Hz), 7.30 (d, 1H, 3-H, J3,4 =8 Hz) 8.08 (d, 1H, 6-H, J4,6 =2 Hz). Anal. (C8H10N2O2) C, H, N.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH2:13][N:14]([CH3:16])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH:17]1([NH:20][C:21](=[O:38])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=2)[CH2:19][CH2:18]1>>[CH:17]1([NH:20][C:21]([C:22]2[CH:27]=[C:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][C:11]([CH2:13][N:14]([CH3:16])[CH3:15])=[N:10][N:9]=4)=[CH:4][CH:3]=3)[C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:38])[CH2:18][CH2:19]1
Reactant: CN(C)Cc1nnc(-c2ccc(I)cc2)o1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN(C)C)o2)cc1

Procedure:
Example 16 was prepared from [5-(4-iodophenyl)-[1,3,4]oxadiazol-2-ylmethyl]-dimethylamine (Intermediate 11) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([NH2:20])[NH:18][N:19]=2)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.C(=O)(OC(C)(C)C)[O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>O.ClCCl>[NH2:20][C:17]1[N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[N:19]=[C:15]([O:14][CH2:13][C:7]2[CH:6]=[C:5]([O:4][CH3:3])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=2)[CH:16]=1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
Potassium hydroxide (11.19 g, 199.4 mmol) dissolved in water (44.8 ml) was added to a solution of 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (7.121 g) dissolved in dichloromethane (40 ml). A solution of (2-methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (6.8 g, 31.2 mmol) in DCM (35 ml) was added and the reaction mixture was stirred vigorously at room temperature for 4 h. The reaction mixture was separated and the organic layer was washed with water (2×15 ml) and brine (2×15 ml), dried over sodium sulphate, filtered, evaporated and dried in vacuo to give tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (8.70 g, 99%) as a cream solid.
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:6][C:7]1[C:8]([C:4]#[C:3][C@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@@H](C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-But-3-yn-2-ol (189 mg, 2.71 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (30 mg, 0.03 mmol) and CuI (2 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and trituration with Et2O. (Yield 40 mg, 47%).
Reaction SMILES: [C:1]1([P:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=C(C)C(OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=C(C=[O:32])N=C1>C(O)C>[C:1]1([P:7](=[O:32])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c[nH]cn1
Reactant: COC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 0.961 g (10 mmol) of methyl 2-(triphenylphosphoranylidene)propionate [H. J. Bestmann and H. Schulz, Angew. Chem., 73, 27 (1961)] and 3.48 g (10 mmol) of imidazole-4-carboxaldehyde [F. L. Pyman, J. Chem. Soc., 186 (1916)] in 50 ml of absolute ethanol is stirred at room temperature for seven days. At the end of this time, the ethanol is removed in vacuo and the desired product is isolated free of triphenylphosphine oxide by chromatography on silica gel. The product thus obtained is a mixture of E and Z olefin isomers.