Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:8])/[CH:3]=[CH:4]/B(O)O.[Na].B(O)O.[NH2:23][C:24]1[N:29]=[C:28]([NH2:30])[C:27](I)=[C:26]([CH3:32])[N:25]=1>C(O)C>[NH2:23][C:24]1[N:29]=[C:28]([NH2:30])[C:27](/[CH:4]=[CH:3]/[C:2]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)([CH3:8])[CH3:1])=[C:26]([CH3:32])[N:25]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: CC(C)(/C=C/B(O)O)c1ccc(C(F)(F)F)cc1
Agent: OBO
Agent: [Na]
Solvent: CCO
Product: Cc1nc(N)nc(N)c1/C=C/C(C)(C)c1ccc(C(F)(F)F)cc1

Procedure:
Example 17, wherein U is alkenylene [e.g., --CH=CHC(CH3)2 --], teaches a desirable method for preparing Compound 68, in which a substituted phenylmethyl halide, for example, 4-trifluoromethylphenylmethyl bromide, is treated with potassium cyanide in water, yielding the corresponding substutited phenylacetonitrile. The so-prepared acetonitrile may then be treated with potassium tert.-butoxide in tetrahydrofuran, then reacted with a lower alkyl halide, for example iodomethane, yielding the corresponding 2-alkyl-2-(substituted phenyl)propanenitrile. The propanenitrile is then treated with diisobutylaluminium hydride which converts it to the corresponding propanaldehyde, for example, 2-methyl-2-(4-trifluoromethylphenyl)propanaldehyde. The propanaldehyde may then be reacted with bromomethyl triphenylphosphonium bromide and potassium tert.-butoxide in tetrahydrofuran, affording the cis/trans-1-bromo-3-alkyl-3-(substituted phenyl)-1-butene intermediate. This compound, in turn can be dehydrohalogenated with potassium tert.-butoxide in tert.-butanol, affording the corresponding butyne, for example, 3-methyl-3-(4-trifluoromethylphenyl)-1-butyne. Using methods taught by G. W. Kabaika et al. [Synthetic Communications, 11(3), 247-251 (1981) and Synthetic Communications, 13(12), 1027-1032 (1983)], the 1-butyne is reacted with 1,3,2-benzodioxaborole to form a boronic acid, in the present case, trans-3-methyl-3-(4-trifluoromethylphenyl)-1-butenylboronic acid. The sodium salt of the boronic acid may in turn be reacted with 2,4-diamino-5-iodo-6-methylpyrimidine in the presence of tetrakistriphenylphosphine palladium(0) in ethanol, yielding the targeted trans-2,4-diamino-6-methyl-5-[3-(4-trifluoromethylphenyl)-3-methyl-1-butenyl]pyrimidine (Compound 68).
Reaction SMILES: [N+:1]([CH:4]=[C:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)SC)([O-:3])=[O:2].[CH3:15][CH:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>>[N+:1]([CH:4]=[C:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:21][CH:16]([CH3:15])[C:17]([CH3:20])([CH3:19])[CH3:18])([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])Nc1ccccc1
Reactant: CC(N)C(C)(C)C
Product: CC(NC(=C[N+](=O)[O-])Nc1ccccc1)C(C)(C)C
Temperature: 100 °C

Procedure:
A mixture of 10.5 g (0.05 mol) of 2-nitro-1-anilino-1-methylthioethene and 15.2 g (0.15 mol) of 1,2,2-trimethylpropylamine was heated at 100° C. for 5 hours. After the mixture had cooled, it was concentrated on a rotary evaporator and the residue was recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26](=[O:27])[CH2:25][CH:24]([C:28]([OH:30])=O)[CH2:23]2)=[CH:18][CH:17]=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26](=[O:27])[CH2:25][CH:24]([C:28]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:30])[CH2:23]2)=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N4CC(C(=O)O)CC4=O)cc3)c2cc1OC
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(N4CC(C(=O)Nc5ccccc5)CC4=O)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-5-oxopyrrolidine-3-carboxylic acid (Step 3, 120 mg, 0.29 mmol), aniline (55 mg, 0.59 mmol), HOBt (58 mg, 0.43 mmol) in 6 mL of DMF was added EDCI (82 mg, 0.43 mmol) at RT. The reaction was stirred at RT for 16 h. The mixture was diluted with 50 mL of EtOAc, and the resulting solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (30% to 100% EtOAc/hexane then to 5% MeOH/EtOAc) to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 484.5 (M+H). Calc'd Exact Mass for C28H25N3O5: 483.52.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[OH-].[NH4+].[H][H]>[Ni].C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C=Cc1ccco1
Reactant: [H][H]
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccco1
Yield: 71.4 %

Procedure:
A mixture of ethyl 3-(2-furanyl)acrylate (46.7 g) and conc. ammonium hydroxide solution (25 ml) was hydrogenated in the presence of Raney Nickel (500 mg) at 35° C. until a theoretical amount of hydrogen was taken up. The Raney Nickel was removed by filtering through diatomaceous earth and the filtrate was evaporated at reduced pressure to yield a brown oil. The oil was dissolved in ethyl acetate, washed with distilled water, dried (MgSO4) and the solvent evaporated at reduced pressure to yield ethyl 3-(2-furanyl)-propionate (33.77 g) as a brown oil.
Reaction SMILES: Br.[CH2:2]([N:20]([CH2:22][CH:23]([OH:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])C)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH:11]([OH:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])C>>[CH2:2]([NH:20][CH2:22][CH:23]([OH:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][CH2:10][CH:11]([OH:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC(O)CN(C)CCCCCCN(C)CC(O)CCCCCCC
Agent: Br
Product: CCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCC

Procedure:
In a manner similar to that of Example 22, methylation of N,N'-(1,6-hexylene)-bis[2-hydroxynonylamine] (36 g.) and treatment of the resulting product (25 g., b.p. 172°-176° C./0.05 mm.) with hydrogen bromide gave N,N'-(1,6-hexylene)-bis[N-methyl-2-hydroxynonylamine] (I: R = CH3 (CH2)6, R' = CH3, X = (CH2)6, Z = H) dihydrobromide (26.3 g., m.p. 176.0°-177.0° C.).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-])=O)(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]>CCO.[Pd]>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[S:21]([N:18]1[CH2:17][CH2:16][N:15]([C:12]2[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:34])([F:33])[F:1])[C:4]([F:5])([F:6])[F:7])=[CH:14][CH:13]=2)[CH2:20][CH2:19]1)(=[O:22])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 4 h
Yield: 65.4 %

Procedure:
To a solution of 1,1,1,3,3,3-hexafluoro-2-(4-(4-(2-nitrophenylsulfonyl)piperazin-1-yl)phenyl)-2-propanol (0.13 g, 0.25 mmol) in EtOH (5 mL) was added 10% palladium on carbon (10 wt % (dry basis) on activated carbon, wet (water about 50%)) (0.026 g, 0.24 mmol). The reaction vessel stirred under a hydrogen atmosphere (1 atm). After 4 hours at room temperature, the reaction vessel was carefully evacuated and backfilled with N2. The solution was filtered through Celite® (diatomaceous earth) and the filtrate was concentrated onto silica. Purification by silica gel chromatography (0 to 6% MeOH in CH2Cl2) afforded 2-(4-(4-(2-aminophenylsulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (79 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.41 (dd, J=1.2, 8.0 Hz, 1H), 7.28-7.35 (m, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.87 (d, J=8.0 Hz, 1H), 6.66 (t, J=7.2 Hz, 1H), 6.09 (s, 2H), 3.22-3.29 (m, 4H), 3.06-3.14 (m, 4H). m/z (ESI, +ve ion) 483.8 (M+H)+. GK-GKRP IC50 (Binding)=0.298 μM; GK-GKRP EC50 (LC MS/MS-2)=0.552 μM.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:26])[CH2:22][CH:23]([CH3:25])[CH3:24]>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: CC(C)CCN
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCC(C)C)ccc1Oc1ccc(C(N)=O)cn1
Yield: 30.4 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (0.0423 g, 0.155 mmol) and isoamylamine (0.020 g, 0.171 mmol) gives the title compound (0.0162 g, 30.3%): TOF MS ES+ 344.2 (M+H)+, HRMS calcd for C19H26N3O3 344.197 (M+H)+, found 344.1949, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=5.9 min, 100% purity.
Reaction SMILES: [NH2:1][C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9]OC(=O)C)[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[OH-].[Na+].[N-:26]=[N+:27]=[N-:28].[Na+]>CC(C)=O.O>[NH2:1][C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][N:26]=[N+:27]=[N-:28])[CH2:7][S:8][C@H:3]12
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (27.2 g, 99.9 mmol) was added water (500 ml) and sodium bicarbonate (9.3 g, 111 mmol); the pH of the mixture was adjusted to 6.5 with 10% sodium hydroxide solution. Sodium azide (13.1 g, 201 mmol) was added to the mixture followed by acetone (350 ml). The mixture was heated at 60° C. for 6 h and left stirring at room temperature overnight. Acetone was removed under reduced pressure and the mixture was cooled in an ice-bath, acidified with concentrated hydrochloric acid to pH 3.5; the precipitated solid was filtered off, dried overnight over P2 05 to give 14.3 g (56%) of 7β-amino-3-azidomethyl-3-cephem-4-carboxylic acid. IR (Nujol) ν max 2095, 1796, 1732 cm-1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:7]([CH3:16])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]([O:15][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[O:14])=[C:7]([CH3:16])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC(=O)Cc1c(C)cc(C(C)(C)C)c(O)c1C

Procedure:
10.68 grams of the compound of Example 5, 11.4 grams of n-octadecanol and 0.8 grams of p-toluene sulfonic acid monohydrate were dispersed in 150 ml of toluene and heated at reflux for seven hours during which the water collected by azeotropic distillation was almost equal to the theory. The reaction mixture was successively washed with water, aqueous saturated sodium bicarbonate solution, and then with water once again until the wash water was neutral. After drying over anhydrous sodium sulfate and filtering free of the drying agent, the clear filtrate was evaporated at reduced pressures to yield the desired product as residue. After successive crystallizations from acetonitrile and n-heptane, the desired compound was isolated as white crystals melting at 57° to 59° C. (Compound 1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([S:11][CH3:12])[CH:5]=[C:4]([CH3:13])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][CH2:22][CH2:23][OH:24]>>[CH3:20][O:21][CH2:22][CH2:23][O:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([S:11][CH3:12])[CH:5]=[C:4]([CH3:13])[N:3]=1
Reactant: CSc1cc(C)nc(Cl)c1[N+](=O)[O-]
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCOc1nc(C)cc(SC)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 5 h

Procedure:
2-Chloro-6-methyl-4-methylthio-3-nitropyridine (2.80 g, 12.81 mmol) was dissolved in 2-methoxyethanol (40 mL). Potassium carbonate (1.90 g, 13.75 mmol) was added to the solution, followed by stirring for 5 hours at 60° C. The mixture was allowed to stand for cooling. Subsequently, the resultant mixture was extracted with ether-water, and the organic layer was washed with saturated brine, followed by drying sodium sulfate anhydrate and concentration under reduced pressure. The obtained residue was purified through silica gel column chromatography [(1) (eluent: n-hexane/ethyl acetate=4/1→n-hexane/ethyl acetate=2/1), (2) (eluent: chloroform)], to thereby yield 2-[(2-methoxyethyl)oxy]-6-methyl-4-methylthio-3-nitropyridine as a pale yellow oil (2.21 g, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([Br:12])[C:3]=1[NH2:4].C(OCC)(=O)C.CN(C)C=O>C(O)C.[Pt]>[NH2:4][C:3]1[C:2]([Br:1])=[CH:8][C:7]([NH2:9])=[CH:6][C:5]=1[Br:12]
Reactant: Nc1c(Br)cc([N+](=O)[O-])cc1Br
Agent: [Pt]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)c(N)c(Br)c1

Procedure:
3.0 g of 2,6-dibromo-4-nitro-aniline are dissolved in 150 ml of ethanol, 150 ml of ethyl acetate and 30 ml of dimethylformamide and, after addition of 0.5 g of platinum-on-charcoal (5%), are hydrogenated in a Parr apparatus at room temperature under a hydrogen pressure of 1.5 bar for 1 hour. After cooling, the mixture is filtered, the solvent is distilled off in a rotary evaporator and the residue is purified by column chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:27])=[C:7]([C:15]([NH:17][C@H:18]([C:20]([O:22]C(C)(C)C)=[O:21])[CH3:19])=[O:16])[C:8](=[O:14])[C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:27])=[C:7]([C:15]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])=[O:16])[C:8](=[O:14])[C:9]2([CH3:12])[CH3:13])=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O)C(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)C1=C(O)c2ccc(Br)cc2C(C)(C)C1=O)C(=O)O
Yield: 55.8 %

Procedure:
1,1-Dimethylethyl N-((7-bromo-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)-L-alaninate (184 mg, 436 μmol) was stirred in TFA (2 mL, 26924 μmol) at room temperature for 30 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (93 mg). MS (m/e)=382.1 (M+H)+. Calculated for C21H19NO5 381.02.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.[CH:48](O)=[O:49]>C(Cl)Cl>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH:48]=[O:49])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: O=CO
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nccn2c(C3CCN(C=O)CC3)nc(-c3cc4ccccc4[nH]3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 432.5 %

Procedure:
To a solution of 1-(1H-Indol-2-yl)-3-piperidin-4-ylimidazo[1,5-α]pyrazin-8-amine hydrochloride (30.00 mg, 0.0068 mmol) in DCM (0.5 ml, 0.008 mol) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.0195 g, 0.102 mmol), N,N-diisopropylethylamine (0.047 mL), 1-hydroxbenzotriaxole hydrate (0.0104 g, 0.0679 mmol) and formic acid (4.7 mg, 0.10 mmol). The reaction was stirred at rt overnight then diluted with DCM, washed with saturated NaHCO3 (2×25 mL) and brine (2×25), then dried over Na2SO4 and concentrated in vacuo. The material thus isolated was crystallized from EtOAc to afford 10.6 mg of desired product. 1H NMR (400 MHz, CDCl3): δ 2.04-2.12 (m, 4H), 2.99-3.00 (m, 1H), 3.27-3.32 (m, 2H), 3.85 (m, 1H), 4.49 (m, 1H), 5.70 (br, 2H), 6.80 (s, 1H), 7.13-7.24 (m, 4H), 7.45 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 8.10 (s, 1H), 8.97 (br, 1H). MS (ES+): m/z 361.16 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:36]([N:39]1[CH2:44][CH2:43][CH:42](O)[CH2:41][CH2:40]1)([CH3:38])[CH3:37]>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH:42]3[CH2:43][CH2:44][N:39]([CH:36]([CH3:38])[CH3:37])[CH2:40][CH2:41]3)[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1ccc2cc(O)ccc2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2cc(OC3CCN(C(C)C)CC3)ccc2n1
Temperature: 35 °C

Procedure:
A mixture of 1 g (0.0046 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl ester, 2.4 g (0.0092 mol) of triphenylphospine (Fluka), 2.4 g (0.0092 mol) of 1-isopropyl-piperidin-4-ol and 1.6 ml (0.0092 mol) of di-tert.-butyl azadicarboxylate 40% in toluene in 100 ml THF was stirred for a prolonged period of time at 35° C. The mixture was filtered through a pad of silica and washed with 30 ml THF. The mixture was evaporated to dryness and purified on silica eluting with a gradient of DCM/MeOH 98/2. The product fractions were evaporated and the residue was triturated with diethyl ether to yield after drying under vacuum 1.3 mg (83%) of the title compound as white solid. MS (m/e): 343.3 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:12]([O:13][C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]([NH:24]C(=O)OCC3C=CC=CC=3)[CH3:23])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:24][C@@H:22]([CH3:23])[CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:36][CH:35]=2)=[N:19][CH:18]=1
Reactant: C[C@@H](COc1ccc(Oc2ccc(OCc3ccccc3)cc2)nc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H](N)COc1ccc(Oc2ccc(O)cc2)nc1

Procedure:
Benzyl {(S)-2-[6-(4-benzyloxyphenoxy)pyridin-3-yloxy]-1-methylethyl}carbamate (118 mg, 0.24 mmol) were hydrogenated in ethanol over 5% of palladium on carbon at 5 bar hydrogen pressure. The catalyst was filtered off and the filtrate was concentrated: Yield: 43 mg (68%), M+H+: 261.13.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:20])[C@@H:12]([OH:19])[C@@H:13]([NH2:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=2[O:2]1.[N:21]1([C:27]([NH:29][C:30]2([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[OH:19][C@@H:12]([C@@H:13]([NH:18][C:36]([C:30]1([NH:29][C:27]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:28])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:37])[CH2:14][CH2:15][CH2:16][CH3:17])[C:11]([NH:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)=[O:20]
Reactant: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Reactant: CCCC[C@H](N)[C@H](O)C(=O)Nc1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)[C@H](O)C(=O)Nc1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 90 %

Procedure:
In anhydrous dichloromethane were dissolved 344 mg (1.23 mmol) of (2S,3S)-N-[(3,4-methylenedioxy)phenyl]-3-amino-2-hydroxyheptanamide, 315 mg (1.23 mmol) of 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid and 233 mg (1.48 mmol) of 1-hydroxybenzotriazole, and then, under nitrogen stream, 284 mg (1.48 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added to the above mixture at 0° C. Thereafter, the temperature of the reaction mixture was returned to room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 80 ml of ethyl acetate, and the resulting mixture was washed successively with water, a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated NaCl solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 574 mg (Yield: 90%) of the desired compound.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:16][C@@H:15]2[C@@H:11]([CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[CH2:10]1)C1C=CC=CC=1.N#N>CO.CCOC(C)=O.[Pd]>[ClH:1].[CH2:12]1[CH:11]2[CH2:10][NH:9][CH2:16][CH:15]2[CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN(Cc3ccccc3)C[C@H]2C1
Agent: [Pd]
Agent: Cl
Agent: N#N
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reaction time: 18 h
Yield: 86.7 %

Procedure:
To a solution of 3-benzyl-7-(tert-butoxycarbonyl)-3,7-diazabicyclo[3.3.0]-octane hydrochloride (91.1 g, 269 mmol; from step (d) above) in methanol (250 mL) under a N2 atmosphere there was added 10% Pd/C (w/w; 9.8 g). The N2 atmosphere was exchanged for H2 (1 atm of pressure) and the reaction was stirred for 18 h. The reaction was filtered through a pad of cellulose to remove the catalyst. The filtrate was concentrated in vacuo to afford an off-white solid. The solid was slurried in EtOAc and collected. After drying in a vacuum oven for 18 h at 60° C./66.5 Pa (0.5 mm Hg) there was obtained 58.0 g (87%) of the title compound as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[OH-].[Li+].Cl>CO>[CH3:14][O:13][C@@H:10]1[CH2:11][CH2:12][C@H:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:15])=[O:2])[CH2:8][CH2:9]1
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@@H](OC)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CO[C@H]1CC[C@@H](C(C)(C)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.200 g of 2-(cis-4-methoxy-cyclohexyl)-2-methyl-propionic acid methyl ester are dissolved in 4 ml of methanol. 4 ml of a 1M aqueous lithium hydroxide solution is added and the mixture is stirred for 16 hours at room temperature. The reaction mixture is then neutralised with 1M HCl and concentrated under reduced pressure. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on its Rf value.
Reaction SMILES: Br.[Br:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>C1COCC1.C(Cl)Cl>[Br:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1)[N:8]=[CH:7]2
Reactant: C1=COCCC1
Reactant: BrCc1ccc2[nH]ncc2c1
Agent: Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: BrCc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
A yellow suspension of 5-(bromomethyl)-1H-indazole hydrogen bromide (compound 12-4, 3.0 g, 14 mmol) and 3,4-dihydro-2H-pyran (Aldrich, 2.4 g, 29 mmol) in THF (100 mL) was heated at reflux temperature for 2 hours. After cooling down to room temperature, the reaction mixture was stirred at room temperature for 12 hours under nitrogen. The reaction mixture was diluted with methylene chloride (250 mL), washed with saturated aqueous NaHCO3, water and brine. After drying (MgSO4), the solvent was removed under vacuum to give a yellow oil. Flash chromatography yielded the title compound (12-5, 3.34 g, 80%). TLC Rf 0.58 (70:30 hexane-ethyl acetate); MS (electrospray) 295, 297 (M+1); 1H N MR (CDCl3) δ 1.57-1.84 (m, 3H), 2.16 (m, 2H), 2.55 (m, 1H), 3.75 (m, 1H), 4.01 (m, 1H), 4.65 (s, 2H), 5.71 (d, 1H, J=9.2 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.59 (d, 1H, J=8.8 Hz), 7.73 (s, 1H), 8.00 (s, 1H).