Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>C(Cl)Cl>[C:25]([O:18][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]([CH3:15])([CH3:17])[CH3:16])(=[O:27])[CH3:26]
Reactant: CC(C)(C)OCCOCC(O)c1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(COCCOC(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.7 %

Procedure:
37.0 g of 1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethanol was dissolved in 70 ml of methylene chloride. To the solution were added 12.9 g of pyridine and 16.6 g of acetic anhydride. The resulting mixture was stirred for 24 hours at room temperature. The reaction mixture was added to a mixture of 150 ml of ice water and 100 ml of methylene chloride. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated, washed with a saturatred aqueous sodium hydrogencarbonate solution and water in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 40.0 g of oily 1-acetoxy-1-(3-chlorophenyl)-2-(2-tert-butoxyethoxy)ethane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.I[CH2:31][CH2:32][CH3:33]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:31][CH2:32][CH3:33])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: CCCI
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccccc1
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
A solution of methyl 2-(2-chloro-4-methyl-6-phenylpyrimidin-5-yl)acetate (2.5 g; 9.03 mmol) in dry DMF (45 mL) was cooled to −15° C. LHMDS (10.84 mL; 10.84 mmol; 1M in THF) was added dropwise and the mixture was stirred at −15° C. for 15 min followed by the dropwise addition of iodopropane (1.765 mL; 18.07 mmol). After stirring for 2 h at −15° C. the mixture was allowed to warm up to room temperature. After 1 h the reaction was quenched by adding a saturated solution of ammonium chloride. The mixture was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (2-20%) in heptane to give 0.98 g (25%) of the title compound as a yellow oil. ESI/APCI(+): 319 (M+H).
Reaction SMILES: C(O)C#CC=CCC.C(O)C#CC#CCC.O1C=CC=C1CN.[CH3:24][C:25]([CH3:33])([CH3:32])/[CH:26]=[CH:27]/[C:28]#[C:29][CH2:30]O.[CH2:34]([NH:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)[CH:44]=1)[CH3:35]>>[CH2:34]([N:36]([CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)[CH:44]=1)[CH2:30][C:29]#[C:28]/[CH:27]=[CH:26]/[C:25]([CH3:33])([CH3:32])[CH3:24])[CH3:35]
Reactant: CCNCCOCCOc1cccc(-c2ccsc2)c1
Reactant: CC(C)(C)/C=C/C#CCO
Agent: CCC#CC#CCO
Agent: CCC=CC#CCO
Agent: NCc1ccco1
Product: CCN(CC#C/C=C/C(C)(C)C)CCOCCOc1cccc(-c2ccsc2)c1

Procedure:
Compound of Example 46 to 49 was obtained by performing the same reaction as in Example 45 except that the corresponding 4-hepten-2-yn-1-ol or 2,4-heptadiyn-1-ol derivative, and 2-furylmethlamine derivative were used instead of the starting compound, (E)-6,6-dimethyl-4-hepten-2-yn-1-ol and N-ethyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine, which were used in the above-mentioned reaction.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20].Cl>C1COCC1>[C:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 63.4 %

Procedure:
To a mixture of 16.5 g (0.101 mol) of 4-hydroxycinnamic acid and 200 ml of a THF solution of 24 ml (0.297 mol) of pyridine was dropwise added 20 ml (0.281 mol) of acetyl chloride over 1 hour at room temperature. After the resulting mixture was stirred at room temperature for 7 hours, the reaction system was poured into 300 ml of a 2N aqueous solution of hydrochloric acid. After extracting with ether and concentrating the organic phase, there was obtained 13.14 g (0.064 mol) of 4-acetoxycinnamic acid as a white solid. The yield was 63%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[F:14].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>ClCCl>[CH3:26][S:27]([O:13][CH2:12][C:9]1[CH:10]=[N:11][C:6]([O:5][C:4]2[CH:15]=[CH:16][C:17]([F:18])=[C:2]([F:1])[CH:3]=2)=[C:7]([F:14])[CH:8]=1)(=[O:29])=[O:28]
Reactant: OCc1cnc(Oc2ccc(F)c(F)c2)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cnc(Oc2ccc(F)c(F)c2)c(F)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of (6-(3,4-difluorophenoxy)-5-fluoropyridin-3-yl)methanol (8.4 g, 26.7 mmol) and triethylamine (6.89 mL, 49.4 mmol) in dichloromethane (DCM) (100 mL) was added methanesulfonyl chloride (4.8 g, 41.9 mmol). The reaction mixture was stirred at 20° C. for 2 hr. then 200 mL of H2O was added. The organic layer was separated, dried over Na2SO4, and then concentrated under reduced pressure to give (6-(3,4-difluorophenoxy)-5-fluoro pyridin-3-yl)methyl methanesulfonate (8 g, 42.3%).
Reaction SMILES: BrC1C=CC(S(O[CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)(=O)=O)=CC=1.[I-:22].[Na+]>CC(C)=O>[I:22][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]1
Reactant: CC1(C)CCC(CCOS(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)CCC(CCI)CC1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 2-(4,4-dimethylcyclohexyl)ethyl 4-bromobenzenesulfonate (Preparation 16, 410 mg, 1 mmol) in acetone (100 ml) was added sodium iodide (370 mg, 2.5 mmol), and the mixture was heated under reflux for 3 h. After allowing the reaction mixture to cool to room temperature, the mixture was filtered and the filtrate was diluted with water (500 ml) and extracted with diethyl ether (500 ml). The organic extract was dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (220 mg, 83%).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][CH:13]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15](OC)=[N:14]3)[C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:26].[NH4+:27]>>[ClH:26].[C:1]1([N:7]2[CH2:11][CH:10]([CH2:12][CH:13]3[NH:14][C:15](=[NH:27])[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(CC2CN(c3ccccc3)N=C2C(F)(F)F)CCCC1
Product: Cl
Product: N=C1CCCCC(CC2CN(c3ccccc3)N=C2C(F)(F)F)N1

Procedure:
The title product of Example 135 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: [C:1]1([CH:7]([Cl:13])[C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:17][CH2:16]1>>[ClH:13].[C:1]1([CH:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[O:14][CH:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[CH2:19][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)c1ccsc1
Reactant: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: Cl
Product: O=[N+]([O-])c1ccccc1OCCCN1CCC(OC(c2ccccc2)c2ccsc2)CC1

Procedure:
The procedure of Example 36 (a) was repeated except for using phenyl-3-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give 4-(phenyl-3-thienylmethoxy)-1-[3-(2-nitrophenoxy)propyl]piperidine hydrochloride.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([N:19]1[CH2:24][CH2:23][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([N:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:4]([O:3][C:1]([N:19]1[CH2:24][CH2:23][C:22]([N:25]([CH3:27])[CH3:26])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:21][CH2:20]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN(C)C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
500 ml (10 equiv.) of Cbz chloride were added dropwise, over a period of 1 hour, to 50 g (1 equiv.) of 1-benzyl-N,N-dimethyl-4-phenylpiperidine-4-amine, and the resulting reaction mixture was stirred for 2 hours at room temperature. The progress of the reaction was monitored by thin-layer chromatography (10% MeOH/CHCl3). When the reaction was complete, the mixture was cooled to 0° C. and rendered basic with saturated sodium hydrogen carbonate solution, and the reaction mixture was extracted 3× with 300 ml of EtOAc. The combined organic phases were dried with Na2SO4. After removal of the solvent under reduced pressure, purification was carried out by column chromatography (silica gel; 50% EtOAc/heptane). 12 g (21%) of product were obtained in the form of an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]#[N:22])=[CH:10][C:9]=2[CH3:23])=[O:4].[CH2:25]([NH:27][CH3:28])[CH3:26]>>[C:21]([C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:23])[CH:10]=1)[N:7]=[C:6]([N:27]([CH2:25][CH3:26])[CH3:28])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)#[N:22]
Reactant: CCNC
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(C#N)cc2c1-c1ccccc1
Product: CCN(C)c1nc2c(C)cc(C#N)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 60 step C from 2-chloro-6-cyano-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 60 step B) and ethyl-methyl-amine. Off-white solid. MS (ESI): 346.2 (M+H)+.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]([OH:52])([CH2:50][CH3:51])[CH2:16][O:17][C@H:18]1[CH2:21][C@H:20]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]3[N:47]=[CH:48][N:49]=[C:23]23)[CH2:19]1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]([OH:52])([CH2:50][CH3:51])[CH2:16][O:17][C@H:18]1[CH2:19][C@H:20]([N:22]2[C:27](=[O:28])[C:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)=[C:25]([CH2:44][CH2:45][CH3:46])[N:24]3[N:47]=[CH:48][N:49]=[C:23]23)[CH2:21]1)[CH3:14]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](OCC(O)(CC)CC)C2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2C[C@H](OCC(O)(CC)CC)C2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.12 g), sodium hydrogen carbonate (0.19 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-3-(2-ethyl-2-hydroxybutoxy)cyclobutyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.06 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.022 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.018 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.052 g, 79%).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([O:10][C:11]([NH:13][CH2:14][C:15]1[C+:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[CH2:24][CH:25]=[C:26]([CH3:28])[CH:27]=[C:19]1[C:18]2([CH3:30])[CH3:29])=[O:12])([CH3:9])([CH3:8])[CH3:7].CO[CH:33](OC)[N:34]([CH3:36])[CH3:35].N12CCCN=C1CCCCC2>CN(C)C=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]([O:10][C:11]([NH:13][CH2:14][C:15]1[C+:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]1[CH2:24][CH:25]=[C:26]([CH:28]=[CH:33][N:34]([CH3:36])[CH3:35])[CH:27]=[C:19]1[C:18]2([CH3:30])[CH3:29])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC1=CCN2C3=CC=C(CNC(=O)OC(C)(C)C)[C+]=C3C(C)(C)C2=C1
Reactant: COC(OC)N(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C=CC1=CCN2C3=CC=C(CNC(=O)OC(C)(C)C)[C+]=C3C(C)(C)C2=C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(tert-Butoxycarbonylamino-methyl)-8,10,10-trimethyl-10H-pyrido[1,2-a]indolylium perchlorate (34 g, 0.077 mol; Sigma-Aldrich) was placed in 1-L round-bottom, one-necked flask equipped with magnetic stir bar and a reflux condenser. 75 mL of dimethylformamide and 38.5 mL of 1,1-Dimethoxy-N,N-dimethylmethanamine (38.5 mL, 0.290 mol; Aldrich) were added to the flask followed by 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.1 g, 0.0006 mol; Aldrich). The flask was immersed in oil bath with temperature set to 100° C. Stirring was started and continued for 30 min. The flask was cooled to room temperature, the solvent was evaporated in vacuum and the residue was recrystallized from methanol. The yield was 29 g (green crystals, 71% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[CH:4][CH:3]=1.[F:26][C:27]([Si](C)(C)C)([F:29])[F:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])([CH3:14])[C:27]([F:29])([F:28])[F:26])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:23])[F:25])=[CH:4][CH:3]=1
Reactant: CC(=O)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2C(F)(F)F)n1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(O)(c1cn(-c2ccc(Br)cc2)c(-c2ccccc2C(F)(F)F)n1)C(F)(F)F
Temperature: 50 °C
Reaction time: 48 h
Yield: 38.9 %

Procedure:
To a solution of 1-[1-(4-bromophenyl)-2-(2-trifluoromethyl-phenyl)-1H-imidazol-4-yl]-ethanone (0.24 g, 0.59 mmol) and trifluoromethyl-trimethylsilane (0.10 mL, 0.68 mmol) in toluene (3 mL, anhyd) at 0° C. was added a 1.0M solution of tetrabutylammonium fluoride (TBAF) in THF (0.12 mL, 20 mol %, dried over 4 Å molecular sieves). After 24 h the reaction mixture was charged with additional trifluoromethyl-trimethylsilane (0.10 mL) and 1.0M TBAF (0.12 mL) and then heated at 50° C. After 48 h (total) the reaction mixture was allowed to cool to ambient temperature, quenched with H2O and extracted with DCM (2×30 mL). The combined extracts were dried (Na2SO4), concentrated and purified by chromatography (silica, EtOAc/Hex, 20:80 to 60:40) to yield the title compound (0.11 g, 39%) as a white solid. 1H-NMR (DCM-d2): δ 7.76 (d, 1H), 7.50-7.60 (m, 2H), 7.46 (d, 2H), 7.27 (m, 2H), 7.02 (d, 2H), 4.36 (s, 1H), 1.72 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:7][C:6]=2[CH:16]=1.[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20].[Cl-].[Li+]>CN1CCCC1=O.O.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>[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:7][C:6]=3[CH:16]=2)=[CH:28][CH:29]=1)=[O:20]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc1
Reactant: CS(=O)(=O)NCc1nc2cc(Br)ccc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)NCc1nc2cc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc3)ccc2s1
Temperature: 90 °C
Yield: 1.6 %

Procedure:
To a stirred solution of N-(5-Bromo-benzothiazol-2-ylmethyl) methane sulfonamide (0.21 g, 0.656 mmol) and 2,2-Difluoro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)-ethyl]acetamide (0.404 g, 0.984 mmol) in N-Methyl-2-pyrrolidone (9 mL) is added lithium chloride (0.084 g, 1.968 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 15 minutes then Pd(PPh3)2Cl2 (0.046 g, 0.065 mmol) is added. The reaction mixture heated to 90° C. for 16 hours. Reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulfate, solvent is evaporated in vacuo to give the crude material purified by flash column chromatography using 2.4% methanol in CH2Cl2 as an eluent to give impure compound. The impure compound is again purified by prep-HPLC to give the title compound (5 mg). 1HNMR (400 MHz, DMSO) δ: 3.04 (s, 3H), 4.26-4.33 (m, 1H), 4.41-4.43 (m, 0.5H), 4.44-4.50 (m, 0.5H), 4.62 (s, 2H), 4.65-4.68 (m, 0.5H), 4.75-4.79 (m, 0.5H), 4.87-4.88 (m, 1H), 5.9 (d, J=4.56 Hz, 1H), 6.20 (d, J=56.36 Hz, 1H), 7.45 (d, J=8.24 Hz, 2H), 7.63, (d, J=8.16 Hz, 1H), 7.73 (d, J=8.28 Hz, 2H). 7.81 (d, J1=1.8 Hz, J2=8.52 Hz, 1H), 8.42 (d, J=1.6 Hz, 1H), 8.82-8.83 (m, 2H). LC-Ms (m/z): [M−H]=485.8.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11]3[N:12]([CH:14]=[CH:15][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[O:24][CH2:25][CH2:26][N:27]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10](=[O:17])[C:11]4[N:12]([CH:14]=[CH:15][CH:16]=4)[CH:13]=3)=[CH:4][CH:3]=2)[CH:29]=[N:28]1
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cn2cccc12
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2ccc(-c3cnn(CCOC4CCCCO4)c3)cc2)cn2cccc12
Temperature: 40 °C
Reaction time: 20 h

Procedure:
Under nitrogen, a suspension of 145 mg (0.50 mmol) 3-(4-bromo-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one, 177 mg (0.55 mmol) 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole and 50 mg (0.60 mmol) sodium hydrogen carbonate in 1 ml DMF and 0.5 ml water is heated to 40° C. Then 7.0 mg (0.010 mmol) bis(triphenylphosphine)palladium(II)-chloride is added. The reaction mixture is heated to 80° C. and stirred at this temperature for 20 hours. The reaction mixture is cooled to room temperature and excess water is added. The resulting precipitate is filtered off and washed with water. The residue is chromatographed on a silica gel column with methanol/dichloromethane as eluent to give 3-(4-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as white powder; HPLC/MS 2.39 min (B), [M+H] 405;
Reaction SMILES: [F:1][C:2]1[C:3]([CH:16]=[CH2:17])=[C:4]([NH:11][CH:12]([CH3:15])C=C)[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]2[C:3]=1[CH:16]=[CH:17][CH:12]([CH3:15])[NH:11]2
Reactant: C=Cc1c(F)ccc([N+](=O)[O-])c1NC(C)C=C
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CC1C=Cc2c(F)ccc([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 64 h
Yield: 65.1 %

Procedure:
To a solution of (3-fluoro-6-nitro-2-vinylphenyl)-(1-methylallyl)amine (134 mg, 0.567 mmol) in DCM (10 mL) was added Grubbs catalyst (2nd generation, benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium) (9.6 mg, 0.011 mmol). The reaction mixture was stirred at RT for 64 h, and then purified by column chromatography (Si—PCC, eluant 1-4% EtOAc in cyclohexane) affording recovered starting material (56 mg) and the title compound (62.8 mg). The recovered starting material was dissolved in DCM (10 mL) and Grubbs catalyst (2nd generation, benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium) (12 mg) was added. The reaction mixture was stirred at 45° C. for 16 h, and then purified by column chromatography (Si—PCC, DCM). The combined products were further purified by column chromatography (Si—PCC, eluant 1.5-4% EtOAc in cyclohexane) affording the title compound as a red solid (76.8 mg, 65%). 1H NMR (CDCl3, 300 MHz): 8.26 (1H, bs), 7.92 (1H, dd, J=9.6, 6.0 Hz), 6.53 (1H, dd, J=10.2, 1.7 Hz), 6.24 (1H, dd, J=9.7, 8.4 Hz), 5.70-5.65 (1H, m), 4.72-4.63 (1H, m), 1.43 (3H, J=6.6 Hz)
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([NH:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:9][C:10]([C:11]([F:14])([F:13])[F:12])=[C:5]2[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3]1.O>C(O)C.[Li+].[OH-]>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:9][C:10]([C:11]([F:13])([F:14])[F:12])=[C:5]2[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3]1
Reactant: COC(=O)CNc1cc(C(F)(F)F)c2c(-c3ccccc3)nn(C)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(NCC(=O)O)nc21
Reaction time: 0.25 h
Yield: 83.6 %

Procedure:
To a solution of methyl 2-(1-methyl-3-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-ylamino)acetate (0.045 g, 0.123 mmol) in ethanol (2.0 mL), aqueous LiOH×H2O (0.026 g, 0.618 mmol in 0.1 mL) was added and stirred at it for 15 min. The organic solvents were removed under reduced pressure and the reaction mixture was acidified with 10% HCl (pH ˜2) to obtain a white solid which was filtered through a funnel and dried under vacuum to yield the title compound as a white solid (0.036 g, 90%). [1H-NMR (DMSO-d6, 300 MHz) δ 7.99 (s, 1H), 7.45-7.38 (m, 5H), 6.85 (s, 1H), 4.15 (d, 2H), 3.92 (s, 3H); LCMS RtC=0.39 min; [M+H]+=351.1]