Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:5]2[C:10]3=[C:11]([C:14]4[CH:15]=[N:16][N:17]([CH3:20])[C:18]=4Br)[N:12]=[CH:13][N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.[C:34](=[O:37])([O-])[O-:35].[Na+].[Na+]>C(O)C.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>[F:21][C:22]([F:33])([F:32])[C:34]([OH:35])=[O:37].[N:1]1([C:5]2[C:10]3=[C:11]([C:14]4[CH:15]=[N:16][N:17]([CH3:20])[C:18]=4[C:26]4[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=4)[N:12]=[CH:13][N:9]3[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cn1ncc(-c2ncn3ncnc(N4CCC4)c23)c1Br
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Product: Cn1ncc(-c2ncn3ncnc(N4CCC4)c23)c1-c1ccc(C(F)(F)F)cc1
Product: O=C(O)C(F)(F)F

Procedure:
4-(Azetidin-1-yl)-5-(5-bromo-1-methyl-1H-pyrazol-4-yl)imidazo[5,1-f][1,2,4]triazine (15 mg, 0.045 mmol), [4-(trifluoromethyl)phenyl]boronic acid (9.50 mg, 0.0500 mmol), tetrakis(triphenylphosphine)palladium(0) (4.6 mg, 0.0040 mmol) and sodium carbonate (9.5 mg, 0.090 mmol) were combined in ethanol (4 mL), and the reaction mixture was heated at reflux for 18 hours. After filtration, the filtrate was concentrated in vacuo and purified via reversed-phase HPLC (Column: Waters Sunfire C18, 19×100 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in acetonitrile (v/v); Gradient: 5% to 100% B). Yield: 4.5 mg, 0.011 mmol, 24%. Retention time: 2.32 minutes (Column: Waters Atlantis dC18, 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in acetonitrile (v/v); Gradient: linear, 5% to 95% B over 4.0 minutes; Flow rate: 2 mL/minute). LCMS m/z 400.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:3]=1[O:4][CH2:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:35])[CH2:18][C@@H:19]([NH:27]C(OC(C)(C)C)=O)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C(C(O)=O)(F)(F)F.O>C(Cl)Cl>[CH3:1][C:2]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:3]=1[O:4][CH2:5][C:6]([NH:8][C@H:9]([C@@H:17]([OH:35])[CH2:18][C@@H:19]([NH2:27])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7]
Reactant: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](N)Cc1ccccc1
Yield: 81 %

Procedure:
(2S, 3S, 5S)-2-(2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-(t-butyloxycarbonylamino)-1,6-diphenylhexane (175.1 g, 0.32 mol) and 500 ml CH2Cl2 were mixed with stirring. CF3CO2H (249 ml, 3.2 mol) was added and stirred 20-25 minutes, then the reaction mixture was poured into a separatory funnel containing 1000 ml of water and 200 ml of CH2Cl2. The resulting mixture was shaken carefully and the layers were separated. The organic layer was washed again with 500 ml of water, then 3×500 ml of NaHCO3 and finally 500 ml of brine. The organic solution was dried over MgSO4, filtered and concentrated to a golden oil that pulled into a foam 300 ml of diethyl ether was added to the crude product and shaken vigorously to dissolve. Within minutes solid began to crystallize and the mixture became thick. Enough diethyl ether was added to make the mixture stirrable and the mixture was stirred at room temperature for 1 hour. The solid was filtered and air dried to give the desired product as 115 g of white needles, 81% yield.
Reaction SMILES: ClC(OC(C)C)=O.[CH3:8][N:9]1CCOC[CH2:10]1.[C:15]([C:18]1[N:19]=[CH:20][N:21]2[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=O)[N:24]=[N:23][C:22]=12)(=[O:17])[NH2:16].Cl.CNC.C(N(CC)CC)C>CN(C)C=O.CCOCC>[CH3:8][N:9]([CH3:10])[C:29](=[O:31])[CH2:28][N:25]1[C:26](=[O:27])[N:21]2[CH:20]=[N:19][C:18]([C:15](=[O:17])[NH2:16])=[C:22]2[N:23]=[N:24]1
Reactant: CN1CCOCC1
Reactant: NC(=O)c1ncn2c(=O)n(CC(=O)O)nnc12
Agent: CC(C)OC(=O)Cl
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Cn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropyl chloroformate (1 M in toluene, 1.155 mL, 1.155 mmol) then N-methyl morpholine (0.127 mL, 1.155 mmol) were added to a stirred solution of 2-(8-carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)ethanoic acid (0.25 g, 1.050 mmol) in dimethylformamide (1.34 mL) under nitrogen at −10° C. to −15° C. After 1 hour, dimethylamine hydrochloride (0.171 g, 2.100 mmol) and then triethylamine (0.292 mL, 2.100 mmol) in dimethylformamide (0.1 mL) were added. The reaction mixture was stirred at −10° C. to −15° C. for one hour then allowed to warm to room temperature. After 40 hours, ether (5 mL) was added and the resulting precipitate was washed with ether (2×5 mL), acetonitrile (2×5 mL), dichloromethane (2×5 mL) and ether (2×5 mL) then purified by flash column chromatography (SiO2, 9:1 acetonitrile/dichloromethane) and preparative HPLC to furnish the title compound. Yield: 23 mg, 0.082 mmol, 8%. LCMS (ES+) m/z 266 (M+H)+ at 0.80 minutes. 1H NMR (400 MHz, d6-DMSO) δ: 8.89 (1H, s), 7.86 (1H, br s), 7.72 (1H, bs), 5.33 (2H, s), 3.10 (3H, s), 2.86 (3H, s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[SH:20][C:21]1[N:25]([CH3:26])[CH:24]=[N:23][N:22]=1>>[CH3:26][N:25]1[CH:24]=[N:23][N:22]=[C:21]1[S:20][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Nc1cnccn1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Cn1cnnc1S
Product: Cn1cnnc1Sc1ccc2ncnc(Nc3cnccn3)c2c1

Procedure:
The compound of Example 3 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, 2-amino-pyrazine and 3-mercapto-4-methyl-1,2,4-triazole.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[CH3:30][O:31][CH2:32][C:33](O)=[O:34]>>[CH3:30][O:31][CH2:32][C:33]([NH:4][C@H:5]([C:10]1[N:11]=[C:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]3)=[C:18]([O:28][CH3:29])[CH:17]=2)[S:13][CH:14]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])=[O:34]
Reactant: COc1cc(Nc2nc([C@@H](N)CC(C)C)cs2)ccc1-n1cnc(C)c1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N[C@@H](CC(C)C)c1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1

Procedure:
The title compound was prepared in analogy to example 34 from 96 mg (0.2 mmol) [4-((S)-1-amino-3-methyl-butyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine trihydrochloride and 20 mg (0.22 mmol) methoxyacetic acid yielding 100 mg (100%) 2-methoxy-N—((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-acetamide as a viscous oil. MS ISP (m/e): 444.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.38 (s, 1H), 7.82 (d, 1H), 7.64 (s, 1H), 7.23 (d, 1H), 7.02 (s, 1H), 6.98 (d, 1H), 6.62 (s, 1H), 4.98 (q, 1H), 3.85 (s, 2H), 3.82 (s, 3H), 2.73 (s, 3H), 2.14 (s, 3H), 1.71 (t, 2H), 1.55 (m, 1H), 0.90 (t, 6H).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:39][C:40]1[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[CH:42][C:41]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: COc1cccc(B(O)O)c1O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1O
Yield: 111.3 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.10 mmol) was treated with (2-hydroxy-3-methoxyphenyl)boronic acid (41 mg, 0.24 mmol), sodium carbonate (26 mg, 0.25 mmols) and bis(triphenylphosphine)palladium(II) dichloride (7 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 71 mg (99% yield) of the title compound. Purity 71%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(S(O[CH2:24][CH2:25][Cl:26])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:24][CH2:25][Cl:26])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1OCCCl
Temperature: 65 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
To a solution of methyl 5-chloro-2-hydroxybenzoate (54.06 g, 0.29 mol) in 300 mL of anhydrous DMF was added 2-chloroethyl 4-methylbenzenesulfonate (81.6 g, 0.35 mol) and Cs2CO3 (142 g, 0.44 mol). The mixture was stirred at 60-70° C. overnight, then water was added. A white solid precipitated from the solution, which was collected by filtration and coevaporated with toluene to afford 76.1 g (88%) of methyl 5-chloro-2-(2-chloroethoxy)benzoate. 1H NMR (400 MHz, CDCl3) δ: 7.76 (d, 1H), 7.40 (dd, 1H), 6.91 (d, 1H), 4.27 (t, 2H), 3.87 (s, 3H), 3.83 (t, 2H).
Reaction SMILES: [OH-].[Na+].C1COCC1.CO.[OH:10][CH:11]([CH2:32][OH:33])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=2)=[CH:16][CH:15]=1>C(O)(=O)C>[OH:10][CH:11]([CH2:32][OH:33])[CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[C:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(C#Cc2ccc(OCC(O)CO)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C#Cc2ccc(OCC(O)CO)cc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 90.9 %

Procedure:
A 10% aqueous solution (5.5 mL) of sodium hydroxide was added to a THF (25 mL)-MeOH (15 mL) solution of methyl 4-{[4-(2,3-dihydroxypropoxy)phenyl]ethynyl}benzoate (0.92 g) as obtained in Example 11-(1), and the mixture was stirred for 3.5 hours at room temperature. Then, acetic acid (1.2 mL) was added for neutralization. The reaction mixture was concentrated, and water was added. The precipitated solid was filtered off and dried to obtain 4-{[4-(2,3-dihydroxypropoxy)phenyl]ethynyl}benzoic acid (light green solid) (0.80 g, 91%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:14](=O)[CH2:15][CH3:16])=[CH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1.C[NH:20][C:21](=[NH:23])[SH:22].S([O-])([O-])(=O)=O.[C:29]([O-])(=O)C.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]([C:6]2[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=2)[N:23]=[C:21]([S:22][CH3:29])[NH:20][C:14]=1[CH2:15][CH3:16])=[O:18]
Reactant: CCC(=O)C(=Cc1cc(Cl)cc(Cl)c1)C(=O)OC
Reactant: CNC(=N)S
Reactant: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1=C(C(=O)OC)C(c2cc(Cl)cc(Cl)c2)N=C(SC)N1
Reaction time: 48 h

Procedure:
1.00 g (3.48 mmol) of 3-(3,5-dichlorophenyl)-2-propionyl-acrylic methylester was dissolved in 10 ml of DMF. 776 mg (2.79 mmol) of methylisothiourea-sulfate and 428 mg (5.22 mmol) of sodium acetate were added at room temperature and stirred at the same temperature for 2 days. After DMF was evaporated under reduced pressure, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in toluene and catalytic amount of silica gel was added and stirred at 100° C. for one day. After filtering silica gel, the filtrate was concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 2/1) to obtain the title compound.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[C:24]([OH:30])[CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[CH2:14]([O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[C:24]([O:30][CH2:10][O:11][CH3:12])[CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cc(OCc2ccccc2)ccc1C=O

Procedure:
N,N-diisopropylethylamine (1.98 ml) and chloromethyl methyl ether (0.76 ml) were added to a solution of 4-benzyloxy-2-hydroxybenzaldehyde (2071 mg) in tetrahydrofuran (30 ml), and this reaction mixture was stirred and heated under reflux for 19 hours. N,N-diisopropylethylamine (2.7 ml) and chloromethyl methyl ether (1.04 ml) were further added, and the resulting mixture was stirred and heated under reflux for another 10 hours. After water was added, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, then filtered through silica gel and alumina. The filtrate was concentrated under reduced pressure to give the title compound (2470 mg). This compound was used in the following reaction without further purification.
Reaction SMILES: C1[C:14]2[C:5](=C[C:7]3[C:12]([CH:13]=2)=CC=CC=3)C=CC=1.CI.[Mg].[CH:18]1[CH2:22][CH:21]=[CH:20][CH:19]=1.[Co+3:23].C/C(/[O-])=C/C(C)=O>C1COCC1>[CH:7]1[CH2:12][CH:13]=[CH:14][CH:5]=1.[CH:19]1([Co:23])[CH:18]=[CH:22][CH:21]=[CH:20]1
Reactant: [Co+3]
Reactant: c1ccc2cc3ccccc3cc2c1
Agent: C1=CCC=C1
Agent: CC(=O)/C=C(/C)[O-]
Agent: [Mg]
Solvent: CI
Solvent: C1CCOC1
Product: [Co]C1C=CC=C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.1 g (6.2 mMoles) of anthracene, 300 ml of THF and 0.1 ml of methyliodide are added with stirring in an inert gas atmosphere at 20° C. to 7.2 g (300 mMoles) of magnesium powder (particle size <0.15 mm). After about 2 hours, the reaction mixture is activated for about 3 hours in an ultrasonic bath (cf. Example 1). The mixture is then heated with stirring to 60° C. After the addition of 52.8 g (800 mMoles) of monomeric cyclopentadiene, the heat source is removed and 35.6 g (100 mMoles) of solid cobalt-(III)-acetylacetonate are added over a period of 30 minutes, the reaction mixture changing color to deep red-brown with a vigorous heat effect (65° C.). After cooling to 23° C., the reaction mixture is filtered off from any insoluble fractions through a G-3-glass frit and the deep red-brown filtrate is concentrated to dryness (max. bath temperature 30° C.) in vacuo (10-1Torr). The residue is taken up in 500 ml of pentane and any insoluble fractions eliminated by filtration. The clear deep red filtrate is concentrated to dryness (max. bath temperature 30° C.) in vacuo (10-1Torr) and the residue sublimated at 10-3Torr (bath temperature up to 60° C., sublimation beginning at a bath temperature of 30° C.). The sublimate is dissolved in approximately 100 ml of pentane and the complex crystallized out at -80° C. 11.9 g (62.6 mMoles=62.6% of the theoretical) of η5 -cyclopentadienyl cobalt cyclopentadiene are obtained in the form of wine-red crystals melting at 98° to 99° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([NH2:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.C(OCC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:16][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[O:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)COc2ccccc2C(N)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(C2=COc3ccccc3C(=O)N2)c1
Yield: 89.7 %

Procedure:
A well stirred suspension of 9 g (31.5 mmol) of 2-[2-(3-Methoxy-phenyl)-2-oxo-ethoxy]-benzamide and 0.3 g (1.58 mmol) of p-toluensulphonic acid in toluene (0.3 L) was refluxed with a Dean-Stark apparatus for 2 hours. After concentration of the solvent under reduced pressure, the residue was treated with ethyl acetate and diethyl ether and the resulting solid was filtered, washed with a mixture of the aforementioned solvents, dried in vacuo, affording 7.55 g of the title compound (83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:41])[F:40])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:37][CH2:36][C:31]4(OCC[O:32]4)[CH2:30][CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH:39]([F:40])[F:41])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:27])[N:28]3[CH2:29][CH2:30][C:31](=[O:32])[CH2:36][CH2:37]3)[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1cn(CC(=O)N2CCC3(CC2)OCCO3)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-2-oxo-ethyl]-1H-pyrazol-4-yl}-amide (46.7 g, 79.5 mmol) in dioxane (280 mL) was cooled in an ice bath before being treated with concentrated hydrochloric acid (210 mL) at a rate which maintained an internal temperature below 22° C. On complete addition, the reaction was allowed to warm to room temperature and stirred for 4 hours. The reaction was cooled in an ice bath, diluted with ethyl acetate and water and the pH of the aqueous phase adjusted to ˜8 by the portionwise addition of solid Na2CO3. The mixture was extracted with ethyl acetate (×4) and the combined organic extract was dried (Na2CO3) and evaporated to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-1H-pyrazol-4-yl}-amide.dioxane as a beige solid (48.8 g, 97%). LCMS (Method 3) [M+H]+=544.2, RT=2.85 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.87 (s, 1H), 8.79 (dd, 1H, J=1.8, 7.0 Hz), 8.70 (s, 1H), 8.57 (dd, 1H, J=1.8, 4.0 Hz), 8.47 (s, 1H), 7.67 (d, 1H, J=2.8 Hz), 7.43 (dd, 1H, J=2.7, 8.7 Hz), 7.29 (d, 1H, J=8.8 Hz), 7.01 (dd, 1H, J=4.3, 7.0 Hz), 6.48 (t, 1H, J=74.0 Hz), 5.14 (s, 2H), 3.93 (t, 2H, J=6.2 Hz), 3.85 (t, 2H, J=6.2 Hz), 3.70 (s, 8H), 2.50 (t, 2H, J=6.2 Hz), 2.42 (t, 2H, J=6.1 Hz).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].[CH2:9]([O:11][CH2:12][Cl:13])[CH3:10]>CC(C)=O.O>[Cl-:13].[CH2:9]([O:11][CH2:12][N+:4]1([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:10]
Reactant: CCOCCl
Reactant: CCCN1CCCC1
Solvent: CC(C)=O
Solvent: O
Product: CCC[N+]1(COCC)CCCC1
Product: [Cl-]
Temperature: 5 °C
Reaction time: 5 h

Procedure:
A 36.22 g quantity of N-propylpyrrolidine was dissolved in 200 g of dehydrated acetone (up to 0.1% in water content), followed by replacement with nitrogen. To the solution was added dropwise 30.25 g of chloromethyl ethyl ether (reagent, product of Tokyo Kasei Co., Ltd. as purified by distillation) at 5° C. over a period of 1 hour. The mixture was stirred at 5° C. for 5 hours, whereby the reaction was terminated. The reaction mixture was filtered, washed with 100 g of acetone and dried in a vacuum, giving 53.30 g of a white solid product.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[S:6]1([C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[NH:9]1)(=[O:8])=[O:7]>C1COCC1>[CH2:1]([C:10]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[S:6](=[O:7])(=[O:8])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCCCC1=NS(=O)(=O)c2ccccc21

Procedure:
This material was prepared by adding 2 equivalents of butyllithium to saccharin in THF at -78° C., followed by aqueous workup at pH 9 as described in the literature by Abramovitch et al., J. Chem. Soc. Perkin I, 1974, 2589.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:14][CH:13]=2)=[CH:9]\[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:35]=[C:34](OC/C=C(/C2C=CC(C#CCN3CCOCC3)=CC=2)\C2C=CC=CC=2)[CH:33]=[CH:32][C:26]=1[O:27][CH2:28][C:29]([OH:31])=[O:30].[C:61]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:14][CH:13]=2)=[CH:9]\[CH2:10][O:11][C:34]2[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29]([O:31][CH3:61])=[O:30])=[C:25]([CH3:24])[CH:35]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(OC/C=C(\c2ccccc2)c2ccc(C#CCN3CCOCC3)cc2)ccc1OCC(=O)O
Reactant: Cc1ccc(-c2ccc(/C(=C/CO)c3ccc(I)cc3)cc2)s1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(-c3ccc(C)s3)cc2)cc1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The above allyl alcohol (0.65 g, 1.50 mmol), methyl (4-hydroxy-2-methylphenoxy)acetate (0.33 g, 1.68 mmol; example 2) and triphenylphosphine (0.48 g, 1.83 mmol) were dissolved in a mixture of anhydrous toluene (30 mL) and tetrahydrofuran (10 mL). The mixture was cooled to 0° C., kept under nitrogen and a degassed solution of diisopropyl azodicarboxylate (0.35 mL, 1.77 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise during 10 min. The reaction mixture was allowed to warm up the ambient temperature with the bath and then was stirred overnight. The solvents were evaporated in vacuo and the residue was submitted to flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 6:1) affording methyl (Z)-[4-[3-(4-iodophenyl)-3-[4-(5-methylthiophen-2-yl)phenyl]allyloxy]-2-methylphenoxy]acetate as solid mass.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)#[CH:18]>>[S:21]1[CH:22]=[CH:23][C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20]1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1ccsc1
Product: O=c1[nH]c2nccc(C#Cc3ccsc3)c2c2ccccc12
Yield: 71.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and 3-ethynyl-thiophene (70 mg, 0.65 mmol) to provide 167 (93 mg, 71% yield) as a white solid. LC-MS (M+H=303, obsd.=303).