Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.CC1=CCCC(C)=CC[C@:13]2(C)[C:25](=[O:26])[C:24](O)=[C:23]([C@@H:28]([CH2:30][OH:31])C)[C@H:14]2[CH2:15][CH:16]=C(C)[C@@H](O)CC1.C(C(CCCCN)C(O)=O)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[O:26]1[C:25]2[C:24](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:23]=[CH:28][C:30]1=[O:31]
Reactant: CC1=CC[C@]2(C)C(=O)C(O)=C([C@H](C)CO)[C@H]2CC=C(C)[C@@H](O)CCC(C)=CCC1
Agent: C/C1=C\C[C@]2(C)C(=O)C(O)=C([C@H](C)CO)[C@H]2C/C=C(\C)[C@@H](O)CC/C(C)=C/CC1
Agent: CC(C)(C)OC(=O)C(CCCCN)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
EDC (1.0 mg, 0.0052 mmol) and DMAP (0.64 mg, 0.0052 mmol) were added to a stirred solution of terpestacin (2.0 mg, 0.005 mmol) and Boc-6-aminohexanoic acid (1.2 mg, 0.0052 mmol) in DMF (2 mL) at 0° C. The reaction mixture was reacted overnight at room temperature. The reaction product was extracted with ethanol (4 mL×3), treated with 20% TFA in CH2Cl2 (1 mL) and stirred at room temperature for 2 hours. DIPEA (1.3 mg, 0.01 mmol) and 6-((7-amino-4-methylcoumarin-3-acetyl)amino)hexanoic acid succinimidyl ester (2.2 mg, 0.005 mmol, MOLECULAR PROBES®) were added thereto at 0° C. After being stirred at room temperature for 4 hours, the reaction product was extracted with ethanol (20 mL) and purified by TLC (CH2Cl2:MeOH=10:1) to obtain coumarin-conjugated terpestacin (yield: 61%). The synthesized coumarin-conjugated terpestacin is depicted in Formula 4.
Reaction SMILES: [NH2:1][NH2:2].CO[C:5](=[O:30])[CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([CH3:25])=[C:12]2[CH2:26][C:27]([NH2:29])=[O:28]>CO.O>[NH2:29][C:27](=[O:28])[CH2:26][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([NH:8][CH2:7][CH2:6][C:5]([NH:1][NH2:2])=[O:30])[CH:10]=2)[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[CH3:25]
Reactant: NN
Reactant: COC(=O)CCNc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Solvent: O
Solvent: CO
Product: Cc1c(CC(N)=O)c2cc(NCCC(=O)NN)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Hydrazine was added to 151 mg (0.4 mmol) of 3-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]amino]propanoic acid methyl ester in 5 mL of MeOH and the mixture heated at reflux for 1.0 hour and stirred at room temperature for 16 hours. After diluting with water, the mixture was extracted with EtOAc, the EtOAc solution washed with saturated NaCl solution, dried (MgSO4) and concentrated at reduced pressure.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:25]4[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4cc(F)cc(F)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3,5-difluorophenylboronic acid (136 mg, 0.86 mmol) the subtitle compound was obtained, (120 mg, 64%). 1H NMR (DMSO) δ 8.70(d, 1H), 8.52(dd, 1H), 8.26(d, 1H), 7.96(d, 1H), 7.88(dd, 1H), 7.69(d, 1H), 7.61(dd, 2H), 7.33(tt, 1H), 4.12(s, 3H). MS 383 m/z (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][C:18]([F:21])([F:20])[CH2:17][C@H:16]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)=O)(C)(C)C>C(Cl)Cl>[Cl:30][C:26]1[CH:25]=[C:24]([NH:23][CH2:22][C@@H:16]2[CH2:17][C:18]([F:21])([F:20])[CH2:19][NH:15]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CNc1cccc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(F)CN[C@H](CNc2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.3 %

Procedure:
TFA (1 mL) was added to the solution of (S)-2-[(3-chloro-phenylamino)-methyl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (0.16 g, 0.0004 mol) in DCM (5 mL) at 0° C. and the reaction mixture was stirred at rt for 12 h. The reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure using a rotary evaporator and washed with ether (3×10 mL). The crude was basified with sodium bicarbonate and the aqueous layer was extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and distilled using a rotary evaporator to give the desired (3-chloro-phenyl)-((S)-4,4-difluoro-pyrrolidin-2-ylmethyl)-amine (0.1 g) as a sticky solid.
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[C:13]([O:20][CH3:21])=[C:12]2[C:8]=1[CH2:9][CH:10]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)[C:11]2=[O:22].Cl>O>[OH:22][CH:11]1[C:12]2[C:8](=[C:7]([O:6][CH3:5])[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[C:13]=2[O:20][CH3:21])[CH2:9][CH:10]1[CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(OCCCCC2Cc3c(OC)c(OC)c(OC)c(OC)c3C2=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(OCCCCC2Cc3c(OC)c(OC)c(OC)c(OC)c3C2O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.9 %

Procedure:
Sodium borohydride (254 mg, 6.72 mmols) was added to a methanol (15 ml) solution of methyl 4-[4-(4,5,6,7-tetramethoxyindan-1-on-2-yl)butoxy]benzoate (1.54 g, 3.36 mmols), with cooling with ice, and then the mixture allowed to warm to room temperature, and stirring was continued for 6 hours. Water was added to the reaction mixture, which was then neutralized with hydrochloric acid added thereto, and thereafter extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo to obtain methyl 4-[4-(1-hydroxy-4,5,6,7-tetramethoxyindan-2-yl)butoxy]benzoate (1.50 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O)=[N+:2]=[N-:3].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:29][C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)=[N+:2]=[N-:3]
Reactant: Oc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCN=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCOc1ccc(Cl)cc1
Temperature: 90 °C
Yield: 56.9 %

Procedure:
7-Azidoheptyltosylate (920 mg, 3.8 mmol) was dissolved in DMF (12 mL). 4-Chlorophenol (650 mg, 5.0 mmol) and K2CO3 (1.7 g, 12.3 mmol) were added and the mixture was heated to 90° C. for 4 h. The mixture was concentrated under reduced pressure, the residue was partitioned between EtOAc (100 mL) and water (25 mL). The organic layer was dried, filtered and concentrated under reduced pressure. Flash chromatography (silica gel, hexanes/EtOAc 95/5) yielded 1-azido-7-(4-chlorophenoxy)-heptane (579 mg, 49%). 1-Azido-7-(4-chlorophenoxy)-heptane (570 mg, 2.1 mmol) was dissolved in EtOH (3 mL). Pd/C (101 mg, 10%) was added and the mixture was stirred under an atmosphere of H2 for 75 min. The reaction mixture was filtered through celite and concentrated under reduced pressure to yield the title compound (453 mg, 89%). The product contained ˜25% of 7-(phenoxy)-heptylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[C:6]([CH2:16][OH:17])([CH2:14]O)[C:5]2=[CH2:18].CS(Cl)(=O)=O.CCN(CC)CC.[OH-].[Na+]>C1COCC1.O.CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[C:6]1([CH2:16][O:17][CH2:14]1)[C:5]2=[CH2:18]
Reactant: C=C1c2cc(Br)ccc2OC(C)(C)C1(CO)CO
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C1c2cc(Br)ccc2OC(C)(C)C12COC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
Under nitrogen, to a solution of (6-bromo-2,2-dimethyl-4-methylene-3,4-dihydro-2H-chromene-3,3-diyl)dimethanol (800 g, 2.55 mol) and MsCl (877.9 g, 7.66 mol) in THF (4.0 L) was added Et3N (851 g, 8.41 mol) over 45 minutes maintaining the temperature below 0-10° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. EtOH (8 L) and NaOH (1021.8 g, 25.55 mol) were added and the reaction mixture was heated under reflux for 16 hours. Water (4 L) was added and a clear solution was obtained. Most of the solvent was removed under reduced pressure and the resulting residue was extracted with ethyl acetate (1.5 L×2). The combined extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in MeOH (640 mL) at 60° C. and the resulting solution was allowed to cool to room temperature. The precipitation formed was filtered-off. The filtrate was concentrated under reduced pressure and the residue was re-dissolved in MeOH (500 mL) at 60° C. The resulting solution was allowed to cool to room temperature and then further to 0-5° C. The mixture was stirred at 0-5° C. overnight and the precipitated yellow solid was collected by filtration to give 6-bromo-2,2-dimethyl-4-methylene-4H-spiro[chromene-3,3′-oxetane] (197.2 g). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=50:1) to give another batch of 6-bromo-2,2-dimethyl-4-methylene-4H-spiro[chromene-3,3′-oxetane] (143.6 g).
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:32][CH:31]([C:33]([OH:35])=O)[CH2:30]2)=[CH:25][CH:24]=1)=[O:21].[CH2:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)C[N:37]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH2:36]([NH:37][C:33]([CH:31]1[CH2:30][N:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])=[CH:24][CH:25]=2)[CH2:32]1)=[O:35])[C:44]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(O)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: O=C(NCc1ccccc1)C1CN(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1C, substituting benzylamine for 3-phenylpropan-1-amine and 1-(4-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)phenyl)azetidine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (s, 1H), 8.53-8.45 (m, 2H), 8.13 (s, 1H), 7.42 (d, J=5.0 Hz, 1H), 7.37-7.22 (m, 7H), 6.43-6.35 (m, 2H), 4.76 (m, 4H), 4.30 (d, J=5.9 Hz, 2H), 3.99-3.88 (m, 2H), 3.83-3.72 (m, 2H), 3.57-3.46 (m, 1H); MS (ESI(+)) m/e 428 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][N:9]1[CH2:13][CH2:12][C@H:11]([O:14][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NN1CC[C@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.2 %

Procedure:
(S)-1-(tert-Butoxycarbonylamino)-3-hydroxypyrrolidine (40 g, 0.21 mol) was dissolved in anhydrous methylene chloride (400 mL), in the presence of N,N-diisopropyl-ethylamine (73 mL, 0.42 mol, 2 equiv.) and cooled using an ice bath. This solution was treated with methanesulfonyl chloride (18 mL, 0.23 mol, 1.1 equiv.) over a 30 min. period and was then allowed to stir at room temperature for 4 h. The solution was concentrated and the residue dissolved in ethyl acetate (250 mL). The resulting organic solution washed with 5% NaHCO3 and then with brine. The organic extract was dried over magnesium sulfate, filtered and concentrated to give (S)-1-(tert-butoxycarbonyl-amino)-3-methanesulfonyloxypyrrolidine as a dark oil (39 g) which was used directly without further purification.
Reaction SMILES: [CH2:1]1[CH2:3][CH:2]1[CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl>>[CH:2]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH:17]3[O:19][CH2:18]3)=[CH:12][CH:13]=2)[CH2:3][CH2:1]1
Reactant: ClCC1CO1
Reactant: Oc1ccc(CCOCC2CC2)cc1
Product: c1cc(OCC2CO2)ccc1CCOCC1CC1

Procedure:
reaction 4-[(2-Cyclopropylmethoxy)-ethyl]-phenol with epichlorohydrin in presence of base to form 1- {4-[2-(Cyclopropylmethoxy)-ethyl]-phenoxy}-2,3-epoxypropane; and
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10]CC)=[O:9])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][CH:7]([CH2:13][CH3:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CC)Oc1ccccc1C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC(Oc1ccccc1C(C)=O)C(=O)O
Yield: 92.7 %

Procedure:
(2-Acetylphenoxy)butanoic acid, ethyl ester (500 mg, 2.00 mmol) is dissolved in 3 mL of methanol/water (3:2) and treated with 828 mg (5.99 mmol) of potassium carbonate according to the procedure described for Example 4 to give 412 mg (93%) of (2-acetylphenoxy)butanoic acid as a white powder. The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 1710, 1670, 1590 cm-1 ; MS m/e calculated for C12H15O4 : 223.0970, found 223.0971.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O[C:13]1([C:25]2[NH:26][CH:27]=[N:28][CH:29]=2)[CH2:22][CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([C:23]#[N:24])[CH:16]=[CH:15][C:14]1=2.[SH:30][CH2:31][CH2:32][OH:33]>C1(C)C(C)=CC=CC=1.C(=O)(O)[O-].[Na+]>[OH:33][CH2:32][CH2:31][S:30][C:18]1[C:19]2[CH2:20][CH2:21][CH2:22][CH:13]([C:25]3[N:26]=[CH:27][NH:28][CH:29]=3)[C:14]=2[CH:15]=[CH:16][C:17]=1[C:23]#[N:24]
Reactant: N#Cc1ccc2c(c1)CCCC2(O)c1cnc[nH]1
Reactant: OCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: N#Cc1ccc2c(c1SCCO)CCCC2c1c[nH]cn1
Temperature: 25 °C

Procedure:
5 mol % p-toluenesulphonic acid are added to a solution of 1 mmol of 5-hydroxy-5-(3H-imidazol-4-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and 2.2 mmol of 2-mercaptoethanol [60-24-2] in 10 ml of xylene, and the mixture is heated to reflux in the presence of molecular sieves (4 Å) overnight. The reaction mixture is cooled to room temperature, diluted with 1M sodium bicarbonate solution and extracted with ethyl acetate (3×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH:24]1(Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>O>[CH:24]1([O:10][C:5]2[CH:6]=[C:7]([C:2]([F:1])=[CH:3][C:4]=2[O:11][CH3:12])[CH:8]=[O:9])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrC1CCCC1
Reactant: COc1cc(F)c(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)c(C=O)cc1OC1CCCC1

Procedure:
A mixture of 6-fluoro-3-hydroxy-4-methoxybenzaldehyde (2 g), potassium carbonate (1.66 g) and anhydrous dimethylformamide (20 mL) is treated with cyclopentyl bromide (1.62 mL) and heated on a steam bath for 43 hours. The mixture is cooled, poured into water (200 mL) and extracted with diethyl ether (3×100 mL). The combined ethereal extracts are washed with sodium hydroxide solution (2×50 mL; 2 N), and brine (2×50 mL), dried over magnesium sulphate and concentrated. The residual brown oil is subjected to flash chromatography [a solvent gradient of 9:1 to 4:1 v/v petroleum ether (b.p. 60–80° C.) and ethyl acetate is used as eluent on a silica gel column] to give 3-cyclopentyloxy-6-fluoro-4-methoxybenzaldehyde (1.42 g) in the form of a yellow oil. [NMR (CDCl3):—10.22(s,1H),7.27(d,1H,J=8 Hz),6.63(d,1H,J=16 Hz), 4.81–4.76(m,1H),3.91(s,3H),2.01–1.57(m,8H)].
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([NH:20]C(OC(C)(C)C)=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].CCOCC>Cl>[C:1]([O:4][CH2:5][C@H:6]([NH2:20])[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][CH3:18])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCCC(C)COc1ccc([C@H](COC(C)=O)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOCC
Product: CCCC(C)COc1ccc([C@@H](N)COC(C)=O)cc1

Procedure:
A solution of (2R)-2-(t-butoxycarbonylamino)-2-(4-(2-methylpentyloxy)phenyl)ethyl acetate (5.50 g, 14.49 mmol) in 2 M HCl in ether (72.5 mL, 144.9 mmol) was stirred at room temperature for 12 h. The precipitate formed was collected on a Buchner funnel, washed with ether, and dried under vacuum to afford (2R)-2-amino-2-(4-(2-methylpentyloxy)phenyl)ethyl acetate.HCl (3.70 g, 81% yield) as a tan solid: 1H NMR (400 MHz, DMSO-d6) δ 8.80 (br. s., 3 H), 7.46 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 4.43-4.55 (m, 1H), 4.25-4.37 (m, 2H), 3.84 (dd, J=9.6, 6.0 Hz, 1H), 3.74 (dd, J=9.6, 6.8 Hz, 1H), 2.05 (s, 3H), 1.81-1.93 (m, 1H), 1.25-1.49 (m, 3H), 1.10-1.23 (m, 1H), 0.96 (d, J=6.5 Hz, 3H), 0.88 (t, J=7.1 Hz, 3H); LRMS (ESI) m/e 280.4 [(M+H)+, calcd for C16H26NO3 280.2].
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[C:31](I)[C:26]=5[N:25]=[N:24]4)[CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[CH3:33][C:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][NH:36][N:35]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>CCO>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[C:31]([C:38]6[C:34]([CH3:33])=[N:35][NH:36][CH:37]=6)[C:26]=5[N:25]=[N:24]4)[CH:20]=[CH:19][N:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(C1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1)N1CCC(O)CC1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1n[nH]cc1-c1cccc2c1nnn2-c1ccnc(NC2CCC(C(=O)N3CCC(O)CC3)CC2)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 11.2 %

Procedure:
A mixture of (4-hydroxy-piperidin-1-yl)-{4-[4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-yl-amino]-cyclohexyl}-methanone (274 mg) and 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg), Na2CO3 (2 M aq, 0.7 mL, degassed), toluene (9 mL, degassed) and EtOH (0.7 mL) was bubbled with argon in a screw cap pressure flask for 10 min. To this was added Pd(PPh3)4 (18 mg), the flask sealed, and the mixture stirred overnight at 110° C. The reaction mixture was allowed to cool to RT, then additional portions of 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg), Pd(PPh3)4 (20 mg), and EtOH (5 mL) were added, the flask sealed, and heated again at 110° C. for 6 h. An additional portion of 3-methyl-pyrazole-4-boronic acid pinacol ester (109 mg) and Pd(PPh3)4 (20 mg) was added, and the mixture stirred at 110° C. overnight. The reaction mixture was then cooled to RT, diluted in water, extracted in DCM, washed with water and brine, dried over Na2SO4, and the solvent stripped to yield a crude solid (311 mg). The crude product (52 mg) was chromatographed on silica, and eluted with 0-60% Magic Base/DCM, titurated in Et2O overnight, filtered, and dried to yield (4-hydroxy-piperidin-1-yl)-(4-{4-[4-(3-methyl-1H-pyrazol-4-yl)-benzotriazol-1-yl]-pyrimidin-2-ylamino}-cyclohexyl)-methanone (Compound 11, 28 mg). mp=190-195° C.; M+H=502.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27](=[O:48])[C:28]1[CH:33]=[C:32]([C:34]#[C:35][Si](C)(C)C)[CH:31]=[CH:30][C:29]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.CCOCC>[CH2:19]([O:26][C:27](=[O:48])[C:28]1[CH:33]=[C:32]([C:34]#[CH:35])[CH:31]=[CH:30][C:29]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[Si](C)(C)C#Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
Tetra-butyl ammonium fluoride (2.97 mL of a 1 M solution in THF, 2.97 mmol) was added to a solution of 2-benzyloxy-5-(2-trimethylsilyl-ethynyl)-benzoic acid benzyl ester (1.07 g, 2.58 mmol) in THF (10 mL) at room temperature. After 30 minutes, the mixture was diluted with ether (20 mL) and washed with water (3×30 mL) and brine (1×30 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (5% ethyl acetate/hexanes) to afford 687 mg (78%) product as a light orange oil. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, 1H, J=2 Hz); 7.52 (dd, 1H, J=9.1, 1 Hz); 7.38 (m, 10H); 6.95 (d, 1H, J=9.1 Hz); 5.35 (s, 2H); 5.19 (s, 2H); 3.0 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][NH2:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C1COCC1.CCOC(C)=O>[C:22]([O:21][C:19](=[O:18])[NH:17][CH2:16][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: NCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1

Procedure:
A solution of C-[4-(4-nitro-phenyl)-tetrahydro-pyran-4-yl]-methylamine (as prepared in the previous step) in THF is treated with BOC2O at RT. The mixture is diluted with EtOAc and washed with water. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with the appropriate solvent to afford the title compound.
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[CH2:6][N:7]1[N:11]=[N:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=2)=[N:8]1>CO.O>[Br:19][C:15]1[N:14]=[C:13]([CH2:12][C:9]2[N:10]=[N:11][N:7]([CH2:6][CH2:5][OH:4])[N:8]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cn1nnc(Cc2cccc(Br)n2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCn1nnc(Cc2cccc(Br)n2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of NaBH4 (92 mg, 2.44 mmol) in MeOH (4.0 mL) at room temperature was added methyl{5-[(6-bromopyridin-2-yl)methyl]-2H-tetrazol-2-yl}acetate (380 mg, 1.22 mmol) in MeOH (6.0 mL). The reaction was stirred at room temperature for 2 h. It was then diluted with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (40-100% EtOAc/hexanes) afforded the title compound as a colorless gum.