Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:26]=[CH:25][C:11]([N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[C:27]1([N:33]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43](B4OC(C)(C)C(C)(C)O4)=[CH:42][N:41]=3)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].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.C1COCC1>[N:6]1[C:5]([C:8]2[CH:26]=[CH:25][C:11]([N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=[C:2]([C:43]2[CH:42]=[N:41][C:40]([C:37]3[CH:38]=[CH:39][C:34]([N:33]([C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:35][CH:36]=3)=[CH:45][CH:44]=2)[CH:7]=1
Reactant: CC1(C)OB(c2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)nc2)OC1(C)C
Reactant: Brc1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)nc1
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: C1CCOC1
Solvent: O
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(-c4ccc(-c5ccc(N(c6ccccc6)c6ccccc6)cc5)nc4)cn3)cc2)cc1
Temperature: 80 °C
Yield: 81.6 %

Procedure:
A mixture of 1 (3.05 g, 7.59 mmol), 2 (3.40 g, 7.59 mmol), tetrakis(triphenylphosphine)palladium(0) (0.438 g, 0.379 mmol), Na2CO3 (7.42 g, 70.0 mmol), H2O (70 mL) and THF (115 mL) was degassed with argon for about 1.25 h while stirring. The stirring reaction mixture was then maintained under argon at 80° C. for about 65 h. Upon confirming consumption of the starting materials by TLC (SiO2, CH2Cl2), the reaction was cooled to room temperature (RT) and poured over CH2Cl2 (400 mL). The organics were then washed with sat. NaHCO3, H2O and brine, dried over MgSO4, filter and concentrated in vacuo. Purification of the crude product via flash chromatography (SiO2, 100% CH2Cl2 to 49:1 CH2Cl2-acetone) provided 3 (3.98 g, 82% yield) as a yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10]O)[C:4]=2[O:3][CH2:2]1.S(Cl)([Cl:14])=O>>[Cl:14][CH2:10][C:9]1[C:4]2[O:3][CH2:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccc2c1OCO2
Reactant: O=S(Cl)Cl
Product: ClCc1cccc2c1OCO2
Yield: 89.1 %

Procedure:
Dissolve benzo[1,3]dioxol-4-yl-methanol (1.9 g, 12.5 mmol) in thionyl chloride (3 mL, 41.1 mmol) and reflux the reaction mixture for 1 h. Concentrate in vacuo to obtain the desired intermediate as a yellow oil (1.9 g, 91%) that was used without further purification. GC-MS m/z: 170 (M+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:18][CH3:19].Cl>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH3:19])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CCI
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Agent: Cl
Product: CCN1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and iodoethane: m.p. 158° C. (HCl). MS m/z (rel. intensity, 70 eV) 267 (M+, 20), 252 (bp), 130 (10), 115 (12), 84 (20);
Reaction SMILES: [Cl:1][CH:2]([CH3:7])[C:3]([NH:5][OH:6])=[NH:4].C(N(CC)CC)C.[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O>C(Cl)Cl>[Cl:1][CH:2]([C:3]1[N:4]=[C:15]([C:16]2[CH:17]=[C:18]([CH3:19])[CH:22]=[CH:23][CH:24]=2)[O:6][N:5]=1)[CH3:7]
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: CC(Cl)C(=N)NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C(C)Cl)no2)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
2-Chloro-N-hydroxy-propionamidine (218 mg, 1.78 mmol) and triethylamine (0.677 ml, 4.86 mmol) were added to 3-methyl-benzoyl chloride (250 mg, 1.62 mmol) in DCM (10.0 ml) at 0° C. and the resulting mixture was stirred for 20 min. The solution was concentrated and DMF (20 ml) was added to the residue and heated at 120° C. for 20 min. The product was purified by flash chromatography using 10-20% EA in hex. affording 0.250 g (59% yield over 2 steps) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)=[CH:18][CH:17]=2)[N:3]=1.[Br:30][CH2:31][CH2:32]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:30][CH2:31][CH2:32][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[CH:20][CH:21]=3)[CH:5]=2)=[CH:9][CH:10]=1
Reactant: Cc1cc(Oc2ccc(Nc3cc(-c4ccc(O)cc4)nc(N)n3)cc2)ccn1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(Nc3cc(-c4ccc(OCCBr)cc4)nc(N)n3)cc2)ccn1
Temperature: 25 °C

Procedure:
To a solution of Step 2 product (1 equiv) in DMF is added 1,2-dibromoethane (1 equiv) and K2CO3 (3 equiv). The mixture is refluxed overnight. After cooling to rt, the mixture is diluted with EtOAc and washed sequentially with 1N NaOH, water and brine. The organic layer is dried (Na2SO4) and concentrated to afford a crude product which is to be used in next step without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[O:8][CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.BrC1C=C2OC=NC2=NC=1.[CH3:21][N:22](C(OC(C)(C)C)=O)[CH:23]([CH2:25][CH:26]=[CH2:27])[CH3:24]>>[CH3:21][NH:22][CH:23]([CH2:25]/[CH:26]=[CH:27]/[C:2]1[N:7]=[C:6]2[O:8][CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1)[CH3:24]
Reactant: Brc1ccc2ncoc2n1
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: Brc1cnc2ncoc2c1
Product: CNC(C)C/C=C/c1ccc2ncoc2n1

Procedure:
5-Bromooxazolo[5,4-b]pyridine, isomeric by orientation of ring fusion to the previously described 6-bromooxazolo[4,5-b]pyridine, can also be used in the Heck coupling with N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine. Subsequent removal of the tert-butoxycarbonyl protecting group provides (4E)-N-methyl-5-(5-oxazolo[5,4-b]pyridinyl)-4-penten-2-amine. The 5-bromooxazolo[5,4-b]pyridine can be synthesized from 3-amino-5-bromo-2-pyridinol (3-amino-5-bromo-2-pyridone) by condensation with formic acid (or a derivative thereof) as described above. 3-Amino-5-bromo-2-pyridinol can be made by bromination (using techniques described by T. Batkowski, Rocz. Chem. 41: 729-741 (1967)) and subsequent thin chloride reduction (according to the method described by S. X. Cai et al., J. Med. Chem. 40(22): 3679-3686 (1997)) of commercially available 3-nitro-2-pyridinol (Aldrich Chemical Company).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([OH:10])[CH2:3]1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:10][CH:4]2[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5]2)=[O:21])=[CH:15][CH:14]=1
Reactant: CC1(C)CC(O)CC(C)(C)C1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CC(OC(=O)Cc2ccc(O)cc2)CC(C)(C)C1
Yield: 48.2 %

Procedure:
3,3,5,5-Tetramethylcyclohexanol (7.81 g, 0.05 mol), 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol), p-toluenesulfonic acid (2 g) and benzene (200 mL) were refluxed with continuous water separation for 8 hours. The reaction mixture was evaporated, the oily residue was dissolved In ethyl acetate (100 mL), washed first with aqueous 5% NaHCO3 solution (100 mL) and then twice with water (200 mL), then dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to give 3,3,5,5-tetramethylcyclohexyl 4-hydroxyphenylacetate as a solid (7.00 g, 82.0% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:19]=[C:20]([C:31]2[CH:36]=[C:35](Cl)[N:34]=[N:33][C:32]=2[CH2:38][CH2:39][CH2:40][CH3:41])[CH:21]=[CH:22][C:23]=1[O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:35]2[N:34]=[N:33][C:32]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:31]([C:20]3[CH:21]=[CH:22][C:23]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:18]([Br:17])[CH:19]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (5.33 mmol, 1.07 g) in THF at room temperature, NaH (100 mg, 4.5 mmol) was added and stirring continued for 30 min then 4-(3-Bromo-4-cyclohexyloxy-phenyl)-3-butyl-6-chloro-pyridazine (3.50 mmol, 1.5 g) was added. The resulting mixture was stirred at 50° C. for over night, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine dried (Na2SO4) filtered and concentrated under reduced pressure. The product was purified by column chromatography using 10-20% ethyl acetate in hexanes to provide 4-[5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (1.6 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:16]([O:18][SiH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])[CH3:17]>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([Si:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:18][CH2:16][CH3:17])=[CH:3][CH:4]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: Brc1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO[Si](OCC)(OCC)c1ccc(Br)cc1
Yield: 81 %

Procedure:
At first, a mixture of 4-iodo-bromobenzene (2.60 g, 9.19 mmol), t-butylammoniumiodido (3.39 g, 9.18 mmol) and [Rh(cod)(CH3CN)2] (105 mg, 0.277 mmol) was added with dimethylformamide (DMF: 26 mL) and triethylamine (2.56 mL, 18.4 mmol). Then, triethoxysilane (1.87 mL, 10.1 mmol) was added dropwise thereto at 0° C. The resultant mixture was stirred under a nitrogen atmosphere at 80° C. for one hour to obtain a reaction mixture. Subsequently, a solvent in the reaction mixture was distilled with a vacuum pump. Under a nitrogen atmosphere, the residue was extracted with ether, filtered with celite, and concentrated to obtain a crude product. Thereafter, the crude product thus obtained was purified by Kugel distillation, and thereby 4-bromo-triethoxysilylbenzene was obtained (2.38 g, 81% yield).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].O.[C:19](Cl)(=[O:21])[CH3:20]>C(OCC)(=O)C>[C:19]([NH:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)(=[O:21])[CH3:20]
Reactant: NC1Cc2ccccc2C1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
To a mixture of 2-aminoindan hydrochloride (10.40 g), potassium carbonate (34.2 g), water (100 ml) and ethyl acetate (150 ml) is added dropwise acetyl chloride (9.68 g) under ice cooling. The mixture is stirred at 0° C. for 1.5 hour, and the ethyl acetate layer is separated, washed with aqueous saline solution, dried, and then the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate - n-hexane to give 2-acetylaminoindan (9.5 g) as colorless crystals. m.p. 126.5°-127.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)[CH:16]=[CH2:15]
Reactant: O=C1CCC(c2ccc(O)cc2)=NN1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(C2=NNC(=O)CC2)cc1
Yield: 80.8 %

Procedure:
A stirred mixture of dry acetone (50 ml), 6-(4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (7 g, 0.037 mole), allyl bromide (3.2 ml, 0.037 mole) and potassium carbonate (5.1 g, 0.037 mole) was heated under reflux for 14 hours. The mixture was diluted with acetone and filtered hot. The inorganic residue was washed with warm acetone and the combined washings and filtrate were evaporated under reduced pressure. The residue was broken up with ether, collected and washed with ether to give 6-(4-allyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (6.88 g, 81%, m.p. 130.5°-132°C). Recrystallisation from methanol gave fine white needles of m.p. 134°-135°C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([C:25]([F:28])([F:27])[F:26])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[CH2:30](O)[CH3:31]>>[CH2:30]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)=[CH:13][C:12]([C:25]([F:28])([F:27])[F:26])=[N:11]2)=[CH:8][CH:9]=1)=[O:3])[CH3:31]
Reactant: CCO
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(C(=O)O)cc2)cc1
Agent: Cl
Product: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
A mixture of 1-(4-carboxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.2 g) and hydrogen chloride in ethanol (50 ml) was refluxed for 6 hours. The solvent was evaporated and the residue was recrystallized from ethanol to give crystals of 1-[4-(ethoxycarbonyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.3 g).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:30][CH2:31][C@H:32]1[O:38][CH:35]([O:36][CH3:37])[CH2:34][C@@H:33]1[OH:39])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>O1CCCC1>[CH2:3]([O:39][C@@H:33]1[C@@H:32]([CH2:31][O:30][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:38][CH:35]([O:36][CH3:37])[CH2:34]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC1C[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC1C[C@H](OCc2ccccc2)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 1.3 g (0.054 mole) of sodium hydride, 10.8 g (7.5 ml, 0.063 mole) of benzyl bromide and 50 ml dry tetrahydrofuran or other aprotic solvent under a dry nitrogen atmosphere were added slowly a solution of 14.8 g (0.038 mole) of crude methyl 2-deoxy-5-O-tritylribofuranoside in 100 ml of dry tetrahydrofuran. After the addition was completed (0.5 hr), the mixture was stirred at ambient temperature for 4 hrs., then at 65°-70° C. for an additional 2 hrs. The mixture was cooled, vacuum filtered through filter-aid, then heated at reflux for 2 hrs. with 15 ml (0.2 mole) of pyridine to consume the excess benzyl bromide. The mixture was again cooled and vacuum filtered through filter-aid. The solvent was removed from the filtrate under reduced pressure. Toluene (2×150 ml) was then added and evaporated. The residue (24.3 g.) was taken up in ethyl acetate (200 ml), washed with saturated NaCl solution (150 ml), then with DI water (150 ml). The organic phase was dried (Na2SO4), filtered and the solvent evaporated under vacuum. The red-orange oil that remained was used directly in subsequent coupling reactions. An analytical sample was prepared by chromatography on silica gel eluting with 10% ethyl acetate in hexane. The light-yellow oil thus prepared showed the following: 1H NMR (CDCl3) δ2.05 (m, 2, CH2), 3.18 (s, 3, OCH3), 3.33 (s, 2, CH2), 3.6 to 4.4 (m, 2, OCH), 4.42 (d, 2, CH2), 4.9 to 5.1 (m, 1, anomeric CH), 7.1 to 7.7 (m, 20, ArH); IR (neat) 3090 cm-1 (w), 3060 (m), 3035 (m), 2920 (m), 1598 (w), 1490 (m), 1448 (s), 1362 (m), 1080 (s), 762 (m), 748 (m), 705 (s), 633 (m).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[C:33](=[O:34])[C:32](I)=[C:31]([O:36][CH3:37])[C:30](=[O:38])[NH:29][C:28]=2[CH:39]=1.[C:40]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=[O:43])[CH:41]=[CH2:42].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:45]([O:44][C:40](=[O:43])/[CH:41]=[CH:42]/[C:32]1[C:33](=[O:34])[C:27]2[CH:26]=[CH:25][C:24]([Cl:23])=[CH:39][C:28]=2[NH:29][C:30](=[O:38])[C:31]=1[O:36][CH3:37])([CH3:48])([CH3:47])[CH3:46]
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1c(/C=C/C(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
A solution of tris(dibenzylidenacetone)dipalladium (O) (0.0163 g) in toluene (39 mL) was treated with tri-orthotolylphosphine (0.0815 g). The solution was stirred under argon at room temperature for 15 minutes and then it was treated with 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (1.22 g) followed by tert-butyl acrylate (7.30 mL, 6.45 g). The mixture was then treated with triethylamine (0.47 mL, 0.34 g) and it was heated to 105° C. for 35 minutes. The mixture was cooled and concentrated to a dark solid. The solid was dissolved in chloroform and chromatographed on a silica gel column (5.5 cm diameter×20 cm long) using 25% ethyl acetate in hexane to give a light yellow solid (0.932 g). A portion of the solid (0.294 g) was dissolved in warm ethyl acetate (5 mL) and then it was concentrated to 3 mL volume. Hexane (1 mL) was added to the solution and crystals formed. The solid was filtered off, washed with cold ethyl acetate, washed with hexane, and dried to give a white solid (0.21 g); mp 213.2°-213.8° C. (dec); 1H NMR (CDCl3) 7.67 (d,1, J=16), 6.61 (d,1, J=16) for trans olefin protons; MS: m/z=308 (base peak), 364 (M+1). Analysis for C18H18ClNO5 : Calculated: C, 59.43; H, 4.99; N, 3.85; Found: C, 59.22; H, 4.92; N, 3.79.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([C:11]#[N:12])[CH:5]=1.Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([N:16]([CH3:17])[CH3:15])=[C:6]([C:11]#[N:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(C#N)c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(C#N)c1
Yield: 94 %

Procedure:
To a stirred solution of 24.0 g (134 mmol) 2 and 240 ml dimethylsulphoxid were added 13.2 g (161 mmol) dimethylamine hydrochloride and 38.9 g (281 mmol) potassium carbonate. The reaction mixture was stirred over night and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude product 3 was obtained in 94% yield (25.7 g, 126 mmol) and was used for the next step without purification.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:35])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([OH:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].Cl(O)(=O)(=O)=O>C(Cl)Cl.C(OC(C)(C)C)(=O)C>[CH2:1]([O:4][C:5]1([CH3:35])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:34][C:5]([CH3:35])([CH3:10])[CH3:6])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](O)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CC(=O)OC(C)(C)C
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Reaction time: 3 h
Yield: 106.6 %

Procedure:
To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (8.5 g, 15.64 mmol) in DCM (250 mL) and t-butyl acetate (175 mL) was added perchloric acid (4.03 mL, 46.9 mmol) at rt. After 3 h, the reaction mixture was diluted with DCM (100 mL), carefully quenched with sat. NaHCO3 (50 mL), organic layer separated and washed with brine (100 mL), dried (Na2SO4), filtered and concentrated to give yellow liquid. This was purified by flash column chromatograpgy on silica gel column using (10-50% EtOAc/Hex as eluant) to afford the desired (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (5 g, 8.34 mmol, 53.3% yield) as light yellow solid. 3 g of starting material was also recovered. 1H NMR (500 MHz, CDCl3) δ 8.23-8.11 (m, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.56-7.51 (m, 1H), 7.33 (t, J=7.9 Hz, 1H), 6.81 (s, 1H), 6.10 (br. s., 1H), 6.00 (br. s., 1H), 5.49 (d, J=16.6 Hz, 1H), 5.28 (d, J=10.2 Hz, 1H), 4.30-4.14 (m, 2H), 4.10-4.00 (m, 2H), 2.65 (s, 3H), 2.09-1.85 (m, 3H), 1.74 (br. s., 1H), 1.38 (s, 3H), 1.28-1.16 (m, 12H). 4 missing piperidine hydrogens. LCMS (M+H)=601.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][C:10]([C:23]([O:25]CC)=[O:24])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=[O:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(Cl)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(Cl)cc2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4.75 g (12.0 mmol) of the compound of Example 55A are provided in 108 ml of 1,4-dioxane, 108 ml (216 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 70° C. for 2 h. The mixture is concentrated, a conc. aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. 4.40 g (100% of theory) of the title compound are obtained.