Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]O.[CH2:6]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].CS(C)=O>O>[CH2:6]([N:10]([CH2:4][CH2:3][CH2:2][Cl:1])[CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNCCCC
Reactant: OCCCCl
Solvent: O
Solvent: CS(C)=O
Product: CCCCN(CCCC)CCCCl
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 9.5 g of 3-chloropropanol, 37 ml of dibutylamine and 50 ml of dimethylsulfoxide was stirred at 70°-80° C. for 8 hours. After cooling, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed from the mixture under reduced pressure. The residue was dissolved in 50 ml of chloroform, and under ice-cooling, 8 ml of thionyl chloride was added dropwise to the solution. After stirring at 50° C. for 3 hours, the solvent was removed from the reaction mixture under reduced pressure. Water was added to the residue and the mixture was washed with diethyl ether. The mixture was made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed from the extract under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform:ethanol=20:1) to give 12 g of N,N-dibutyl-3-chloropropylamine (yield: 58%, oily product).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:11][CH3:12])[O:9][CH3:10].O(CC)CC.C([Li])CCC.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[O:30])[CH:24]=1>CCCCCC>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:29]([C:25]1[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=1)[OH:30]
Reactant: O=Cc1cccnc1
Reactant: COC(OC)c1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COC(OC)c1ccccc1C(O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To a stirred and cooled (-78° C.) mixture of 50 parts of 1-bromo-2-(dimethoxymethyl)benzene and 245 parts of 1,1'-oxybisethane were added dropwise 59 parts of a 1-butyllithium solution 2.5M in hexane. Upon complete addition, stirring was continued for 10 minutes at room temperature. A solution of 23.1 parts of 3-pyridinecarboxaldehyde in 42 parts of 1,1'-oxybisethane was added dropwise to the reaction mixture. Upon completion, the mixture was allowed to reach room temperature. The mixture was taken up in ice water and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated, yielding 56 parts (99.9%) of α-[2-(dimethoxymethyl)phenyl]-3-pyridinemethanol as a residue (intermediate 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.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>[Cl:30][C:31]1[CH:36]=[C:35]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[C:5]([C:8]3[CH:9]=[CH:10][N:11]=[C:12]4[C:17]=3[CH:16]=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]4)[CH:4]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F)C(F)(F)F
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1cccc(Cl)c1
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A mixture of trifluoromethanesulfonic acid 2-fluoro-5-(7-trifluoromethyl-[1,8]naphthyridin-4-yl)phenyl ester (30.0 mg, 0.068 mmol), 3-chlorobenzeneboronic acid (13.9 mg, 0.089 mmol), dichlorobis-(triphenylphosphine)palladium(II) (5.0 mg, 7.1 μmol) and 2 M sodium carbonate solution (0.5 mL) in DME (3 mL) was irradiated in a microwave reactor at 150° C. for 10 min. After cooling to room temperature, the mixture was diluted with dichloromethane (3 mL) and water (3 mL), and was filtered through a PTFE cartridge. The separated organic phase was concentrated in vacuo, and the residual material was purified by preparative thin layer chromatography on silica gel, eluting with 5% ethyl acetate in dichloromethane, affording 5-(3′-chloro-6-fluorobiphenyl-3-yl)-2-trifluoromethyl[1,8]naphthyridine as a white solid (12.7 mg, 46%). δH (360 MHz, CDCl3) 7.33-7.50 (5H, m), 7.57 (1H, dd, J 1.8 and 7.0), 7.59-7.60 (2H, m), 7.84 (1H, d, J 8.8), 8.54 (1H, d, J 8.8), 9.29 (1H, d, J 4.2). m/z (ES+) 403, 405 [MH]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:24]3[CH:25]=[CH:26][NH:27][C:23]=3[CH:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1.CN(C)[CH:30]=[O:31].[NH4+].[Cl-]>O1CCCC1.CCCCCC>[NH:27]1[C:23]2[CH:22]=[CH:21][N:20]=[C:19]([N:16]3[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][C:5]4[C:4]5[C:8](=[CH:9][CH:10]=[C:2]([CH:30]=[O:31])[CH:3]=5)[NH:7][CH:6]=4)[CH2:14][CH2:15]3)[C:24]=2[CH:25]=[CH:26]1
Reactant: Brc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1
Reaction time: 1 h

Procedure:
A solution at −78° C. of 1.5 mmol of the compound obtained in Step 3 in tetrahydrofuran is treated with 9 mmol of tert-butylithium (1.8M in hexane). After stirring the mixture for 1 hour, 12 mmol of dimethylformamide are added and the mixture is brought to ambient temperature. After reaction for 4 hours, the solution is hydrolysed by a saturated solution of NH4Cl and then extracted with dichloromethane. After treating the organic phase in conventional manner, chromatography of the residue on silica gel enables the expected product to be isolated.
Reaction SMILES: O1CCOC1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)OC(C)(C)C)=[C:9]([NH:21][C:22]2[N:27]=[C:26]([NH:28][C@H:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=[O:39])[CH2:31][CH2:30]3)[C:25]([N+:40]([O-:42])=[O:41])=[CH:24][N:23]=2)[CH:8]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][C:9]=1[NH:21][C:22]1[N:27]=[C:26]([NH:28][C@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32](=[O:39])[CH2:31][CH2:30]2)[C:25]([N+:40]([O-:42])=[O:41])=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCC(=O)c3ccccc32)n1
Solvent: C1COCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(F)cc1Nc1ncc([N+](=O)[O-])c(N[C@@H]2CCC(=O)c3ccccc32)n1

Procedure:
A solution of 1,3-dioxolane of (R)-tert-butyl 4-fluoro-2-(5-nitro-4-(4-oxo-1,2,3,4-tetrahydronaphthalen-1-ylamino)pyrimidin-2-ylamino)phenylcarbamate (145 mg) and TFA (2.5 mL) in CH2Cl2 (5 mL) was stirred at room temperature for 1 h. Volatiles were removed in vacuo and the crude (120 mg) was subjected to the next step without further purification.
Reaction SMILES: O=S(Cl)Cl.[CH3:5]O.[OH:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12]>C(OCC)(=O)C>[OH:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([O:13][CH3:5])=[O:12]
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Reactant: CO
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100 %

Procedure:
SOCl2 (0.6 mL) was added dropwise to anhydrous MeOH (10 mL) at 0° C. The mixture was stirred at this temperature for 0.5 h, then 3-hydroxy-2-nitrobenzoic acid (0.6 g, 3.2 mmol) was added to the mixture. The resulting mixture was heated at reflux for 4 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The resulting mixture was concentrated in vacuo to give the title compound (0.63 g 100%) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15](COCCOC)[C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([S:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].Cl.O1CCOCC1>CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:22]=[C:23]([Cl:34])[C:24]([S:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3n2COCCOC)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
To a mixture of 1-[5-benzylsulfanyl-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (96.0 mg, 0.192 mmol) and EtOH (5 mL) was added 4M HCl in dioxane (5 mL, 20 mmol). The mixture was stirred for 18 h at 23° C. The reaction mixture was concentrated under reduced pressure and the resulting residue was triturated in Et2O. The resultant suspension was filtered and washed with Et2O to yield the titled compound (69.0 mg, 87%). MS (ESI/CI): mass calcd. for C20H17ClN4O2S, 412.1; m/z found, 413.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.53 (d, J=12.3 Hz, 1H), 8.95 (s, 1H), 8.35 (s, 1H), 7.78 (s, 0.5H), 7.65 (s, 0.5H), 7.55 (s, 0.5H), 7.44 (s, 0.5H), 7.38 (d, J=7.2 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 7.25 (s, 1H), 4.32-4.26 (m, 4H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:5][C:4]=1[S:22](Cl)(=[O:24])=[O:23].C(OCC)(=O)C.Cl>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:5][C:4]=1[S:22]([NH2:1])(=[O:24])=[O:23]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)c1=O
Reactant: N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(S(N)(=O)=O)c2)c1=O

Procedure:
With stirring, 1.6 g (93.8 mmol) of ammonia gas were, at 0° C., introduced into a mixture of 18 g (44.6 mmol) of 2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-(2H)-pyrimidin-1-yl]-benzenesulfonylchloride in tetrahydrofuran (THF). Then, at 10° C., ethyl acetate was added and the mixture was acidified with 1N hydrochloric acid. The phases were separated and the aqueous phase was extracted, and the combined organic phases were then washed, dried and the solvent was removed. Customary purification methods gave 14.4 g (82.4% of theory) of the title compound (m.p.: 257-258° C.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[NH:24][C:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:28]([F:41])[CH:27]=1.O>O1CCCC1>[S:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:28]([F:41])[CH:27]=1
Reactant: COc1ccc(-c2nc3ccccc3s2)c(NC(=O)c2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc3ccccc3s2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
To a suspension of lithium aluminum hydride (90 mg) in tetrahydrofuran (5 ml) was added dropwise a solution of N-(2-benzothiazol-2-yl-5-methoxyphenyl)-3-fluoro-4-(2-piperidin-1-ylethoxy)benzamide (300 mg) in tetrahydrofuran (1 ml) on an ice bath, and the solution was stirred for 4 hours at room temperature. To the reaction mixture were sequentially added tetrahydrofuran (10 ml), water (0.14 ml), an aqueous solution of 5N sodium hydroxide (0.14 ml) and water (0.42 ml) on an ice bath, the resulting suspension was filtered, and the filtrate was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-chloroform system) to provide the title compound (120 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:29][C:30]1[CH:35]=[C:34](I)[CH:33]=[CH:32][N:31]=1.[Cl-].[NH4+]>O1CCCC1.O>[Cl:29][C:30]1[CH:35]=[C:34]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][CH2:7]2)[CH:33]=[CH:32][N:31]=1
Reactant: Clc1cc(I)ccn1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(c2ccnc(Cl)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 31.3 %

Procedure:
A solution of piperidine-1,4-dicarboxylic acid 1-tert-butylester 4-ethyl ester (200 g, 0.78 mol, 1 equiv.) in dry tetrahydrofuran (350 mL) was added a 1M solution of sodium bis(trimethylsilyl)amide (1010 mL, 1.01 mol, 1.3 equiv.) drop-wise at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 1.5 h at 0° C. and added to a solution of 2-chloro-4-iodopyridine (199.2 g, 0.83 mol) in dry tetrahydrofuran (350 mL) at 0° C. under nitrogen atmosphere. The reaction mixture was kept at 0° C. for 3 hours, and was monitored by TLC (ethyl acetate/petroleum ether; 1/5). A solution of ammonium chloride (34.8 g) in water (260 mL) was added cautiously. The formed two layers were separated in a separation funnel. The organic layer was extracted, dried over anhydrous sodium sulfate and concentrated. The resulting dark oil was purified by flash chromatography on silica gel to obtain the oil 1-tert-butyl 4-ethyl 4-(2-chloropyridin-4-yl)piperidine-1,4-dicarboxylate (90 g, 32% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1)=[O:6].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH3:14][C:9]1[CH:8]=[C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:10]=1[CH3:13]
Reactant: Cc1ccc(C(=O)CCCCl)cc1C
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(C)c(C)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme 81 using 4-chloro-1-(3,4-dimethylphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 407.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C@@H:31]([C:33]2[CH:34]=[C:35](B(O)O)[C:36]([F:39])=[N:37][CH:38]=2)[CH3:32])[C@@H:27]([CH3:43])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C([O-])(=O)C.[K+].CO>O1CCOCC1.ClCCl.O.[Cl-].[Na+].O>[F:39][C:36]1[N:37]=[CH:38][C:33]([C@H:31]([N:28]2[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[CH2:26][C@@H:27]2[CH3:43])[CH3:32])=[CH:34][C:35]=1[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: Cc1nc(Cl)c2ncn(C3CCCCO3)c2n1
Reactant: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1nc(-c2cc([C@@H](C)N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)cnc2F)c2ncn(C3CCCCO3)c2n1
Temperature: 120 °C
Yield: 80.2 %

Procedure:
A glass microwave reaction vessel was charged with 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.200 g, 0.791 mmol) and 5-((R)-1-((S)-4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (0.407 g, 1.108 mmol) in dioxane (3 mL). Then A-Phos (0.056 g, 0.079 mmol), potassium acetate (0.233 g, 2.374 mmol) and water (0.5 mL) was added into the reaction mixture. The reaction mixture was stirred and heated in a CEM Explorer Microwave at 120° C. for 10 min (120 watts, Powermax feature on). The mixture was diluted with dichloromethane (10 mL), water (10 mL) and brine solution (5 mL). The organic layer was collected by extracting with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give the crude material as tan oil. The crude material was adsorbed onto silica gel and purified by chromatography through a silica-gel column (40 g) eluting with 100% ethyl acetate, then with 10% methanol in dichloromethane to give (3S)-tert-butyl 4-((1R)-1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)-3-methylpiperazine-1-carboxylate (0.342 g, 0.634 mmol, 80% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 8.26-8.35 (m, 3H) 5.86 (dd, J=10.37, 2.35 Hz, 1H) 4.19 (d, J=11.74 Hz, 2H) 3.83 (d, J=2.54 Hz, 1H) 2.89 (s, 3H) 2.54 (d, J=2.93 Hz, 2H) 2.16 (s, 1H) 2.11 (s, 1H) 2.07 (d, J=17.80 Hz, 1H) 1.81 (d, J=11.54 Hz, 2H) 1.59-1.75 (m, 3H) 1.39-1.49 (m, 15H) 1.02 (d, J=5.67 Hz, 3H). m/z (ESI, +ve ion) 540.2 (M+H).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1[C:12]([CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([CH:20]=[O:21])[NH:10][C:9]=1[CH3:22])=[O:7])C.Cl>CO.O>[CH:20]([C:11]1[NH:10][C:9]([CH3:22])=[C:8]([C:6]([OH:7])=[O:5])[C:12]=1[CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:17])=[O:18])=[O:21]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCS(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1[nH]c(C=O)c(CCCS(C)(=O)=O)c1C(=O)O
Temperature: 65 °C
Yield: 86.8 %

Procedure:
Lithium hydroxide (179.6 mg, 7.5 mmol) was added to a suspension of 5-formyl-4-(3-methanesulfonyl-propyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (450 mg, 1.5 mmol) in methanol (6 mL) and water (6 mL). The mixture was heated under nitrogen in a 65° C. oil bath for 20 hours. The cooled reaction was adjusted to pH 2 using 1N HCl, the resulted precipitate was collected by vacuum filtration, washed with water and dried to give 356 mg (87%) of 5-formyl-4-(3-methanesulfonyl-propyl)-2-methyl-1H-pyrrole-3-carboxylic acid.
Reaction SMILES: [CH:1]1([C:6]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:19]3[CH2:18][C:17]4[C:12](=[CH:13][C:14]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:16]=4)[C:11]=3[CH:10]=[C:9]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.CCCCCC.C([Li])CCC.Cl[Si:52]([CH3:55])([CH3:54])[CH3:53]>C1COCC1.O>[CH3:53][Si:52]([CH3:55])([CH3:54])[C:3]1[CH:4]=[CH:5][CH:1]([C:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:7]2[C:19]3[CH2:18][C:17]4[C:12](=[CH:13][C:14]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:16]=4)[C:11]=3[CH:10]=[C:9]([C:24]([CH3:26])([CH3:27])[CH3:25])[CH:8]=2)[CH:2]=1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C(c3ccccc3)(c3ccccc3)C3C=CC=C3)c1C2
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C(c3ccccc3)(c3ccccc3)C3C=CC([Si](C)(C)C)=C3)c1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
To a solution of 0.45 g (0.88 mmol) of 1-(cyclopentadienyl)-1(3,6-di-tert-butylfluorenyl)diphenylmethane in 30 ml of THF, 0.54 ml (0.97 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 16 hours. After the resulting solution was cooled to −78° C., a solution of 0.22 ml (1.76 mmol) of chlorotrimethylsilane in 10 ml of THF was slowly added, followed by stirring at room temperature for 6 hours. To the reaction solution, 20 ml of water was added to terminate the reaction. The resulting solution was subjected to extraction with diethyl ether, then dried over anhydrous magnesium sulfate and vacuum evaporated to dryness to obtain a yellow solid. The solid was washed with a small amount of methanol and dried under reduced pressure to obtain 0.42 g of an opaque white solid (yield: 81.8%) The analyzed values are given below.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:4]([F:7])([F:6])[F:5].Br[CH2:28][CH2:29][CH2:30][OH:31].C([O-])([O-])=O.[Cs+].[Cs+].[I-].[K+]>CC(C)=O>[F:1][C:2]([F:25])([F:26])[C:3]([C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:28][CH2:29][CH2:30][OH:31])([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:4]([F:6])([F:5])[F:7]
Reactant: OCCCBr
Reactant: COc1ccc(COC(c2cccc(O)c2)(C(F)(F)F)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: COc1ccc(COC(c2cccc(OCCCO)c2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
1.12 g (2.9 mmol) of 3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenol (example 5) in 20 ml of acetone were treated with 0.51 mL (5.9 mmol) of 3-bromo-1-propanol in the presence of 1.9 g (5.9 mmol) Cs2CO3 and 245 mg (1.5 mmol) of potassium iodide. The reaction mixture was stirred at 50° C. overnight, filtered and evaporated. The crude product was redissolved in EtOAc and a 1M KHSO4 solution, the phases were separated and the inorganic one extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and the solvent was evaporated. Column chromatography on silica gel yielded 1.1 g (84%) of 3-{3-[2,2,2-trifluoro-1-(4-methoxy-benzyloxy)-1-trifluoromethyl-ethyl]-phenoxy}-propan-1-ol as a colorless liquid, MS: 438 (M)+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].CS(Cl)(=O)=O.C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2].[I-:30].[Na+]>ClCCl>[I:30][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: [I-]
Reactant: CCCc1ccc(CO)cc1
Agent: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1ccc(CI)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
(4-propylphenyl)methanol (100 mg, 0.666 mmol) was dissolved in 3 mL of well-dried dichloromethane (DCM) under argon condition and then cooled to 0° C., and methanesulfonyl chloride (MsCl; 62.1 μL, 0.799 mmol) and triethylamine (Et3N; 140 μL, 0.999 mmol) were added thereto. Upon completion of the reaction after stirring for 30 minutes at 0° C., the reaction was terminated by adding 5 mL of water. The reaction mixture was extracted with DCM (3 mL×3), and the organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out, and the resulting solution was concentrated by distillation under reduced pressure. The residue was dissolved again in 6 mL of acetone and then sodium iodide (NaI; 150 mg, 0.999 mmol) was added thereto. Upon completion of the reaction after stirring for 15 minutes at room temperature, the solvent was dried by distillation under reduced pressure. 10 mL of water was added to the residue and the mixture was extracted with ethyl acetate (5 mL×3). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out, and the resulting solution was concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 157 mg (0.604 mmol, 90%) of the desired compound (tag β reporter unit).