Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: Cn1cc(C2(O)CCC(=O)CC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:25])[NH:6][C:7]1[N:8]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:9]=[C:10]([C:12]([CH2:16][F:17])([CH3:15])[CH2:13][F:14])[CH:11]=1.CCN(C(C)C)C(C)C.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([O:50][C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]([NH2:61])=[CH:53][N:52]=2)[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].O>CS(C)=O>[C:37]([O:41][C:42]([N:44]1[CH2:45][CH2:46][CH:47]([O:50][C:51]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:54]([NH:61][C:5]([NH:6][C:7]3[N:8]([C:18]4[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=4)[N:9]=[C:10]([C:12]([CH2:16][F:17])([CH3:15])[CH2:13][F:14])[CH:11]=3)=[O:25])=[CH:53][N:52]=2)[CH2:48][CH2:49]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncc(N)c3ccccc23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Add [5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Preparation 27, 2.7 mmol, 1.2 g) and DIPEA (2.9 mmol, 0.5 mL) to a solution of 4-(4-amino-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 22, 2.9 mmol, 1.0 g) in 4 mL of DMSO and stir at 85° C. overnight. Cool down, add water and extract with dichloromethane. Combine the organic layers and wash with saturated aq. sodium chloride. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate in gradient (from 15 to 70%) to yield 4-(4-{3-[5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS ES+ (m/z) 635 [M+H].
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=1.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:20][C:19]=2B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14]1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:20][C:19]=2[C:2]2[N:7]3[CH:8]=[N:9][CH:10]=[C:6]3[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=2)[CH2:14][CH2:15]1
Reactant: Cn1cc(Br)n2cncc2c1=O
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3cncn23)c1
Yield: 21.6 %

Procedure:
To a microwave vial containing 5-bromo-7-methylimidazo[1,5-a]pyrazin-8-one (150 mg, 0.66 mmol), 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (290 mg, 0.80 mmol) and NaHCO3 (1 mL, 2M) in dioxane (3 mL) was added Pd(dppf)Cl2 (80 mg, 0.10 mmol). The mixture was purge with N2 for 2 min and sealed. The reaction was irradiated in microwave at 100° C. for 2 h. Water (20 mL) was added and the mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried with Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (PE: EA=5:1 to 1:1) to afford the title compound (55.3 mg, 22%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.03 (dd, J1=8.4 Hz, J2=2.0 Hz, 2H), 7.94 (d, J=2.0 Hz, 1H), 7.56 (s, 1H), 7.15 (d, J=8.8 Hz, 1H), 6.49 (s, 1H), 3.96 (d, J=6.4 Hz, 2H), 3.54 (s, 3H), 3.16 (q, J=7.6 Hz, 1H), 1.33 (t, J=7.6 Hz, 1H), 1.08 (s, 1H), 0.54 (d, J=7.2 Hz, 2H), 0.54 (d, J=4.4 Hz, 2H). LCMS: 388.1 (M+1)+
Reaction SMILES: C(OC([N:8]1[CH2:31][CH2:30][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][CH:17]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1)=O)(C)(C)C.[CH2:32]([O:36]C=C)[CH2:33]CC.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC=C)=C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[N:12]1[C:11]2[CH2:30][CH2:31][NH:8][CH2:9][C:10]=2[CH:15]=[N:14][C:13]=1[C:16]1[CH:17]=[CH:18][C:19]([C:32](=[O:36])[CH3:33])=[CH:20][CH:21]=1
Reactant: C=COCCCC
Reactant: CC(C)(C)OC(=O)N1CCc2nc(-c3ccc(OS(=O)(=O)C(F)(F)F)cc3)ncc2C1
Agent: [Pd+2]
Agent: C=COC=C
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2ncc3c(n2)CCNC3)cc1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 2-(4-trifluoromethanesulfonyloxy-phenyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester (918 mg, 2.0 mmol) in dry DMF (10 ml) is added n-butylvinyl ether (1.02 g, 10 mmol, 5.0 eq.), TEA (404 mg, 4.0 mmol, 2.0 eq.), 1,3-bis(diphenylphosphino)propane (29 mg, 0.055 mmol, 0.0276 eq.) and palladium acetate (11.3 mg, 0.05 mmol, 0.025 eq.) under nitrogen. The resulting mixture is stirred at 80° C. for 7 hr. Water (30 ml) is added to quench the reaction, and the mixture is extracted with EtOAc (30 ml×3). The combined organic phase is washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified by silica gel flash chromatography (hexane/EtOAc 5:1) to give a mixture of the vinyl ether and the ketone product, which is dissolved in EtOAc (30 ml), and then treated with concentrated hydrochloric acid (3.0 ml). The mixture is stirred at rt for 2 hr, and then basified with saturated sodium carbonate solution. The organic phase is collected, and the aqueous phase is extracted with DCM twice. The combined organic phase is dried over sodium sulfate, and concentrated to give the title compound. MS (+VE) m/z 254.1 (M++1).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35]>>[OH:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:29][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[N:6][CH:5]=1)=[O:28]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Reactant: NCCOCCO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCOCCO)cn2)CC1
Yield: 79 %

Procedure:
By the same procedure as described in the example 25, the synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using 2-(2-aminoethoxy)ethanol. And then, the product was recrystallized with acetone and hexane to give a desired compound.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.C(N(C(C)C)C(C)C)C.[NH:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20].[NH:32]([CH3:52])[C@H:33]([C:38]([NH:40][C@H:41]([C:43]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44])[CH3:42])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36]>C(Cl)(Cl)Cl>[NH:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:18]([C:22]([N:32]([CH3:52])[C@H:33]([C:38]([NH:40][C@H:41]([C:43]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44])[CH3:42])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:24])[CH:19]([CH3:20])[CH3:21]
Reactant: CN[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)Cc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)Cc1ccccc1)N(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 2 h

Procedure:
12.9 ml (12.7 g=106 mMol) pivaloyl chloride and 23 g (212 mMol) N-ethyl-diisopropylamine are added to a solution of 23.2 g (106 mMol) BOC-L-Val-OH in 400 ml chloroform and the mixture stirred for 2 hrs. at room temperature under a nitrogen atmosphere. 27.37 g (89 mMol) H-MeLeu-Ala-Bzl dissolved in 100 ml chloroform are then added and the reaction mixture stirred for a further 18 hrs. at 60° C. again under a nitrogen atmosphere. The obtained solution is washed with 300 ml 1N HCl, the aqueous phase extracted with 200 ml methylene chloride and the combined organic phases washed 2× with 200 ml saturated potassium carbonate solution. The aqueous phases are extracted with 200 ml methylene chloride, the combined organic phases dried over potassium carbonate, filtered and concentrated. The residue is chromatographed on 2 kg silica gel 60 (0.065-0.2 mm) with 1% methanol in methylene chloride as eluant to yield the title compound as a colourless oil: rotation [α]D25 =-97.2 (c=1.0 in chloroform).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].Cl[CH2:18][CH2:19][S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1)(=[O:22])=[O:21].Cl>CN(C=O)C.C(OCC)(=O)C.O>[F:32][C:29]([F:30])([F:31])[C:25]1[CH:24]=[C:23]([S:20]([CH2:19][CH2:18][S:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])(=[O:21])=[O:22])[CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(CCCl)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccnc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(O)c1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
683 mg (4.92 mmol) of K2CO3 were added to a suspension of 349 mg (2.25 mmol) of 2-mercaptonicotinic acid in DMF (5 ml), and the mixture was stirred for 30 min at RT. 614 mg (2.25 mmol) of 2-chloroethyl-(3-(trifluoromethyl)phenyl)sulfone were then added, and stirring was continued for a further 72 h at RT. The reaction solution was concentrated in vacuo, the residue obtained was taken up in ethyl acetate, and water was added. The pH was adjusted to 3 with 2 M hydrochloric acid, and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. 778 mg (1.99 mmol, 88%) of 2-(2-(3-(trifluoromethyl)phenylsulfonyl)ethylthio)nicotinic acid were obtained as residue.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]([N:7](CC1C=CC=CC=1)[CH3:8])[CH3:6]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]([NH:7][CH3:8])[CH3:6]
Reactant: COC(=O)CC(C)N(C)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC(C)CC(=O)OC
Reaction time: 16 h

Procedure:
3-(Benzyl-methyl-amino)-butyric acid methyl ester (15 g, 67.8 mmol, 1.0 equiv) was placed in a Parr hydrogenation bottle and dissolved in 50 mL of MeOH. 20% Palladium hydroxide on carbon (0.5 g, 0.94 mmol, 0.014 equiv) was added and the mixture was shaken at 50 psi H2 for 16 h. The reaction was judged as complete when the uptake of H2 had stopped. The bottle was opened and 10 g of diatomaceous earth in 100 mL of MeOH was added. The mixture was filtered on a pad of diatomaceous earth which was then washed with 2×100 mL of MeOH. The filtrates were combined and concentrated in vacuo to yield the desired product as an oil that is somewhat volatile (7.6 g, 85%). The crude product was used without further purification; MS, m/z 132=M+1.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[F:13][CH2:14][C:15]([CH2:17][F:18])=O.N1CCCC1>CO>[F:8][C:6]1[CH:5]=[C:4]2[C:3](=[C:2]([F:1])[CH:7]=1)[O:12][C:15]([CH2:17][F:18])([CH2:14][F:13])[CH2:10][C:9]2=[O:11]
Reactant: CC(=O)c1cc(F)cc(F)c1O
Reactant: O=C(CF)CF
Solvent: CO
Solvent: C1CCNC1
Product: O=C1CC(CF)(CF)Oc2c(F)cc(F)cc21
Yield: 80.9 %

Procedure:
A solution of 1-(3,5-difluoro-2-hydroxyphenyl)ethanone (4.98 g, 28.9 mmol), MeOH (50 mL), 1,3-difluoroacetone (5.44 g, 57.9 mmol), and pyrrolidine (4.79 mL, 57.9 mmol) was heated at 60° C. for 20 hours. The dark solution was cooled, concentrated, chased with toluene, and then passed through a silica gel plug, washing with toluene (200 mL) and MTBE (200 mL). The filtrate was washed with 2N NaOH (50 mL×2), dried (Na2SO4), filtered, and concentrated to afford the title compound (5.80 g, 23.37 mmol, 81%), which was used without further purification in the next step. MS (DCI) m/z 299 (M+51)+.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([CH:18]1[O:20][CH2:19]1)Br>>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:16][CH:18]2[CH2:19][O:20]2)=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Reactant: BrCC1CO1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Yield: 21 %

Procedure:
Synthesis followed SP3a, using 4.1 mmol 4-(tert-Butyl-dimethyl-silanyloxy)-phenol and racemic epibromohydrine to give the title compound upon purification by Flash Master Personal (20 g silica gel cartridge, PE to PE/ethyl acetate 15:1) with 21% yield.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=O.COCCO[AlH2-]OCCOC.[Na+].O>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2
Reactant: O=C1NCCc2c(F)cccc21
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc2c1CCNC2
Reaction time: 18 h

Procedure:
5-Fluoro-3,4-dihydro-2H-isoquinolin-1-one (200 mg, 1.2 mmol) was dissolved in anhydrous tetrahydrofuran (6 ml), and the solution was mixed with Red-Al (Aldrich, 65% toluene solution, 6.1 mmol) and stirred at roar temperature for 18 hours. Water was slowly added to the reaction solution, and celite filtration was carried out when foaming started. The reaction product was extracted from the filtrate with ethyl acetate, and the reaction product was extracted from the extract with dilute hydrochloric acid. The water layer was alkalified with sodium hydroxide aqueous solution, and the reaction product was extracted therefrom with ethyl acetate. The extract was washed with saturated brine and dried with anhydrous magnesium sulfate, and then the solvent was removed by evaporation under a reduced pressure to obtain crude 5-fluoro-3,4-dihydro-2H-isoquinoline. The crude 5-fluoro-3,4-dihyrdro-2H-isoquinoline was dissolved in anhydrous N,N-dimethylformamide (3 ml), and the solution was mixed with 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (370 mg, 1.2 mmol) and potassium carbonate (250 mg, 1.8 mmol) and stirred at room temperature for 18 hours. The reaction solution was mixed with water, the reaction product was extracted with ethyl acetate, and the extract was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the extract under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 55 mg (0.14 mmol, 12% in yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[N:14]([CH3:39])[C:15]3[C:20]([N:21]=2)=[C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:18]=[C:17]([N:28]2[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[N:30]=[C:29]2[CH2:37][CH3:38])[N:16]=3)([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:43]>C1COCC1>[CH2:37]([C:29]1[N:28]([C:17]2[N:16]=[C:15]3[C:20]([N:21]=[C:13]([C:10]4([O:12][CH3:43])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]4)[N:14]3[CH3:39])=[C:19]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:18]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[N:30]=1)[CH3:38]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Reaction time: 16 h
Yield: 57.5 %

Procedure:
To a solution of 3-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (208 mg, 0.39 mmol) in THF (3 mL) was added NaH (19 mg, 0.47 mmol, 60% dispersion in mineral oil) and the mixture allowed to stir for 5 min before the addition of iodomethane (29 μL, 66 mg, 0.47 mmol). The resulting mixture was allowed to stir for 3.5 h before further iodomethane (29 μL, 66 mg, 0.47 mmol) was added. The mixture was stirred for 16 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 40-80%) affording 714 as an oil (123 mg, 57%). LCMS (method I): RT 4.49 min, [M+H]+ 549.2. 1H NMR (CDCl3, 400 MHz): δ 7.99-7.90 (1 H, m), 7.74-7.64 (1 H, m), 7.25-7.16 (2 H, m), 4.60-4.40 (4 H, brd m), 4.18 (2 H, d, J=9.17 Hz), 3.82-3.81 (6 H, m), 3.71 (3 H, s), 3.29 (2 H, t, J=7.54 Hz), 3.07 (3 H, s), 1.42-1.33 (12 H, m).
Reaction SMILES: [CH:1](=[N:5]/[C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])\[CH2:2][CH2:3][CH3:4].C[Si](C)(C)[O:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CC1CCCO1>[CH2:23]([O:22][C:18]([O:19][CH2:20][CH3:21])([C@@H:1]([NH:5][C@H:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:7])[CH2:2][CH2:3][CH3:4])[C:17]([O:25][CH2:26][CH3:27])=[O:16])[CH3:24]
Reactant: CCOC(OCC)=C(OCC)O[Si](C)(C)C
Reactant: CCC/C=N/[C@@H](C)c1ccccc1
Solvent: CC1CCCO1
Product: CCC[C@H](N[C@@H](C)c1ccccc1)C(OCC)(OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 4 h
Yield: 119.2 %

Procedure:
With BF3OEt2: (S,E)-N-butylidene-1-phenylethanamine (Example 1, 10.0 g, 57.0 mmol) was dissolved in 250 mL 2-methyltetrahydrofuran and cooled to 0° C. BF3OEt2 (7.0 mL, 57.0 mmol) was added to the mixture followed by a solution of trimethyl((1,2,2-triethoxyvinyl)oxy)silane (Example 10, 11.34 g, 45.6 mmol) in 80 mL 2-methyltetrahydrofuran, and the mixture was stirred at 0° C. After four hours, further imine (1.8 g, 10.2 mmol) and BF3OEt2 (1.2 mL, 9.7 mmol) were added and the mixture was stirred at 0° C. for further three hours. The volume of the mixture was halved by evaporation, water was added, the mixture was neutralized (pH=7.2) with 2N NaOH, and the phases were separated. Removal of the solvent in vacuo yielded 19.1 g crude (S)-ethyl 2,2-diethoxy-3-(((S)-1-phenylethyl)amino)hexanoate as a 85.15 (syn:anti) diastereomeric mixture.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Product: CCC(=O)NC1CCCc2c(-c3ccc(Cl)cc3)cncc21
Yield: 86 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-1) was reacted with 4-chlorophenylboronic acid to give the title compound as light yellow foam in 86% yield. MS: 315.5 (M+H+, 1Cl).
Reaction SMILES: C([O:8][C:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=[C:11]2[O:19][C@H:20]3[CH2:46][N:23]([C:24](=[O:45])[C@H:25]([C:38]4([CH3:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[NH:26][C:27](=[O:37])[O:28][C@@H:29]4[CH2:36][C@H:30]4[CH2:31][CH2:32][CH2:33][C:34]#[C:35][C:10]=12)[C@H:22]([C:47]([O:49][CH3:50])=[O:48])[CH2:21]3)C1C=CC=CC=1>CO.C1COCC1.[Pd].ClCCl>[CH3:44][C:38]1([C@H:25]2[C:24](=[O:45])[N:23]3[CH2:46][C@@H:20]([CH2:21][C@H:22]3[C:47]([O:49][CH3:50])=[O:48])[O:19][C:11]3=[N:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:9]([OH:8])=[C:10]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]3[CH2:36][C@H:29]3[O:28][C:27](=[O:37])[NH:26]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1(C)CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCC#Cc1c(nc3ccccc3c1OCc1ccccc1)O2
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1(C)CCCCC1)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1O)O2
Yield: 93.4 %

Procedure:
A solution of the product of step 4 (870 mg, 1.280 mmol) in MeOH (8532 μl) and THF (4266 μl) was treated with a catalytic amount of 10% palladium on carbon (68 mg). The mixture was hydrogenated at 30 psi. After 6 hours LCMS showed complete reaction. The mixture was diluted with dichloromethane (50 mL) and the solids were removed by filtration. The filtrate was concentrated in rotavap and the residue was purified on a gold cap RediSep® (80 g) silica gel column (gradient: 0 to 40% ethyl acetate in hexanes) to give the title compound (710 mg, 1.196 mmol, 93% yield) as a white powder.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[C:30]1([C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>ClCCl.C(OCC)C>[C:30]1([C:36]([C:2]2[N:3]=[CH:4][N:5]([C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:6]=2)([OH:40])[CH2:37][CH2:38][CH3:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCCC(=O)c1ccccc1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC(O)(c1ccccc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 200 mg (0.46 mmol) 4-iodo-1-trityl-imidazole in 3 ml anhydrous dichloromethane was added at ambient temperature 0.16 ml (0.48 mmol) 3M ethyl magnesium bromide in diethyl ether. The mixture was stirred for 1 hour then a solution of 55 mg (0.37 mmol) 1-phenyl-butan-1-one in 0.1 ml anhydrous dichloromethane was added in one portion and the reaction mixture was stirred for 16 hours. Saturated aqueous ammonium chloride (5 ml) was then added to the reaction mixture and the whole was extracted with dichloromethane (3×5 ml). The organic phase was washed with water (3×5 ml) then brine (3×5 ml), dried over MgSO4, concentrated and purified by preparative HPLC to give 90 mg rac-1-phenyl-1-(1-trityl-1H-imidazol-4-yl)-butan-1-ol as colourless oil: MS (ISP): 459.0 ((M+H)+.); 1H-NMR (CDCl3): 0.80 (3H, t, CH3), 1.30 (2H, m), 2.05 (2H, m, CH2), 3.45 (1H, s, br, OH), 6.70 (1H, s), 7.05-7.45 (21H, m).