Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N+:11]([O-])[CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C-:24]#[N:25].[K+].C(Cl)(=O)C1C=CC=CC=1.O.C(Cl)(Cl)Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([C:24]#[N:25])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(-c2cc[n+]([O-])nc2-c2ccc(OC)cc2)cc1
Agent: [K+]
Solvent: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(-c2cc(C#N)nnc2-c2ccc(OC)cc2)cc1
Yield: 64 %

Procedure:
A solution of 3,4-bis-(4-methoxyphenyl)pyridazine 1-oxide [Eur. J. Med. Chem.-Chimica Therapeutica, 14, 53-60 (1979)] (5.01 g, 16.25 mmol) and potassium cyanide (3.17 g, 48.75 mmol) in water (90 ml) was ice-cooled. After benzoyl chloride (7.77 g, 55.25 mmol) was added dropwise with vigorous stirring under a nitrogen gas atmosphere, the resulting mixture was stirred at room temperature for 20 hours. Water-chloroform was added to the reaction mixture, and subsequent to alkalinization, the thus-obtained mixture was extracted with chloroform. The organic layer was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue (oil) was separated and purified by chromatography on a silica gel column [hexane/ethyl acetate (5/1)]. Relevant fractions were crystallized from ethyl acetate-diethyl ether-hexane, whereby the title compound was obtained as slightly yellow prisms (3.30 g, 64.0%). Melting point: 113-115° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].[CH2:9]([Li])CCC.CI.O>O1CCCC1>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)([CH3:9])[CH3:2]
Reactant: CCc1ccccn1
Reactant: [Li]CCCC
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccccn1
Temperature: -20 °C

Procedure:
A solution of 19.4 ml (0.17 mol) of 2-ethylpyridine in 100 ml of tetrahydrofuran was cooled to −20° C. and 125 ml of n-butyllithium (1.6M in hexane, 0.2 mol) were subsequently added while stirring. The mixture was allowed to come to room temperature, stirred for another one hour and subsequently cooled back down to −20° C. A solution of 18 ml (0.25 mol) of methyl iodide in 20 ml of tetrahydrofuran was then added at such a rate that the temperature remained at −20° C. The mixture was allowed to warm to room temperature, stirred for a further 14 hours and hydrolyzed with 60 ml of water. The organic phase was separated off and the aqueous phase was extracted three times with 50 ml each time of diethyl ether. The organic phases were combined, dried over magnesium sulfate, the magnesium sulfate was filtered off and the solvent was distilled off. The residue obtained in this way was distilled at 81-84° C./60 torr. This gave 10.88 g (53%) of 2-isopropylpyridine.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([C:20](Cl)=[O:21])[C:11]3=[O:23])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:24]1(=[O:31])[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[CH2:25]1.C(N(CC)CC)C.Cl>ClCCl.CC(C)(O)C#N.O.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([C:20]([C:25]4[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:24]=4[OH:31])=[O:21])[C:11]3=[O:23])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)c1nc2ccccc2n(-c2ccc3c(c2)OCO3)c1=O
Reactant: O=C1CCCC(=O)C1
Agent: CC(C)(O)C#N
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CCCC(O)=C1C(=O)c1nc2ccccc2n(-c2ccc3c(c2)OCO3)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
The 1-(benzo[d][1,3]dioxol-5-yl)-2-oxo-1,2-dihydroquinoxaline-3-carbonyl chloride thus obtained was dissolved in dichloromethane (30 mL), and the solution was added dropwise to a liquid mixture containing 2.7 g (24 mmol) of 1,3-cyclohexanedione, 3.7 g (36 mmol) of triethylamine and dichloromethane (20 mL), under ice-cooling. After stirring the reaction solution for 3 hours at room temperature, 0.04 g (0.53 mmol) of acetone cyanohydrin and 3.7 g (36 mmol) of triethylamine were added to the liquid mixture, and the mixture was stirred for 12 hours at room temperature. The reaction solution was poured into water, and the aqueous layer was acidified with 10% hydrochloric acid, and extracted with dichloromethane. The obtained organic layer was dried over anhydrous magnesium sulfate, and the inorganic matter was separated by filtration. The solvent was distilled off under reduced pressure, and to the residue thus obtained, a mixed solution of methanol and water was added to obtain a solid. The solid was collected by filtration and dried, to obtain 5.5 g (yield: 75%) of 1-(benzo[d][1,3]dioxol-5-yl)-3-(2-hydroxy-6-oxo-1-cyclohexenecarbonyl)-quinoxalin-2(1H)-one as a yellow amorphous matter.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([N:22]([CH3:28])[CH2:23][C:24]([F:27])([F:26])[F:25])=O)[CH:18]=3)[N:13]=[C:12]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].B.C1COCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][N:22]([CH3:28])[CH2:23][C:24]([F:27])([F:25])[F:26])[CH:18]=3)[N:13]=[C:12]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(CC(F)(F)F)C(=O)c1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a mixture of 4-(3-chloro-4-fluorophenylamino)-N-methyl-2-(pyridin-3-yl)-N-(2,2,2-trifluoroethyl)quinazoline-6-carboxamide (60 mg, 0.12 mmol) THF (1 mL) was added BH3-THF (2 mol/L, 1 mL). The mixture was stirred at room temperature overnight. Methanol (0.2 mL) was added to quench the reaction mixture. The mixture was purified by prep-HPLC to give the desired product N-(3-chloro-4-fluorophenyl)-6-((methyl(2,2,2-trifluoroethyl)amino)methyl)-2-(pyridin-3-yl)quinazolin-4-amine (GL0001H-3309) as a white solid 15 mg in a yield of 26.0%. LCMS: r.t=2.154 min, [MH]+=476.1. 1H-NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.53 (s, 1H), 8.70-8.66 (m, 2H), 8.44 (s, 1H), 8.27-8.25 (m, 1H), 7.93-7.91 (m, 3H), 7.57-7.55 (m, 2H), 3.93 (s, 2H), 3.39-3.32 (m, 2H), 2.40 (s, 3H).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[O:28]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1>>[O:28]1[C:32]2([CH2:37][CH2:36][N:35]([C@H:2]3[CH2:19][C@@:18]4([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]5[C@@H:17]4[CH2:16][CH2:15][C@@:13]4([CH3:14])[C@H:9]5[CH2:10][C@H:11]([N:22]5[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)[C@@H:12]4[OH:21])[CH2:4][C@@H:3]3[OH:1])[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Product: C[C@]12C[C@H](N3CCC4(CC3)OCCO4)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Yield: 79.88 %

Procedure:
2α,3α-Epoxy-16β-(1-piperidinyl)-5α-androstane-17β-ol is reacted with 1,4-dioxa-8-azaspiro[4.5]decane as described in Example 3 to give the title compound in a yield of 79.88%, m.p.: 216°-218° C.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:7]2[CH:31]=[C:30]([OH:32])[C:10]3[C:11]4[CH2:29][CH2:28][S:27][C:12]=4[C:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:14][C:9]=3[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1.[O:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40](O)=[O:41])[CH2:35][CH2:34]1.C1(N=C=NC2CCCCC2)CCCCC1>>[CH:1]1([CH2:4][CH:5]([C:7]2[CH:31]=[C:30]([O:32][C:40](=[O:41])[CH2:39][N:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)[C:10]3[C:11]4[CH2:29][CH2:28][S:27][C:12]=4[C:13]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:14][C:9]=3[CH:8]=2)[CH3:6])[CH2:3][CH2:2]1
Reactant: O=C(O)CN1CCOCC1
Reactant: CCCCCCC1(CCCCCC)Oc2cc(C(C)CC3CC3)cc(O)c2C2=C1SCC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCC1(CCCCCC)Oc2cc(C(C)CC3CC3)cc(OC(=O)CN3CCOCC3)c2C2=C1SCC2

Procedure:
By reacting 7-(3-cyclopropyl-2-propyl)-1,2-dihydro-9-hydroxy-4-oxo-4H-thieno[2,3-c] [1]benzopyran with n-hexyl magnesium bromide, using the procedure described above in Example 8, there is obtained 7-(3-cyclopropyl-2-propyl)-4,4-di(1-hexyl)-1,2-dihydro-9-hydroxy-4H-thieno[2,3-c] [1]benzopyran. The benzopyran is then reacted with morpholinoacetic acid and dicyclohexylcarbodiimide according to the method of Example 9 to yield the desired ester.
Reaction SMILES: C(OCCCCCCC=C)(=O)C.O1C2CCC=CCCC12.[C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]1O[CH:37]1[CH2:38][CH2:39][CH2:40][CH3:41])(=[O:24])[CH3:23].C[Si](C)(C)[Si](C)(C)C.C[O-].[K+]>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]/[CH2:38][CH2:39][CH2:40][CH3:41])(=[O:24])[CH3:23]
Reactant: CCCCC1OC1CCCCCCCCCCOC(C)=O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: C1=CCCC2OC2CC1
Agent: C=CCCCCCCOC(C)=O
Product: CCCC/C=C/CCCCCCCCCCOC(C)=O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
FIG. 4 shows the reaction path for producing E-11-hexdecenyl acetate. To a dry 50-mL round-bottomed flask is added 4.5 g (0.026 mol) 7-octenyl acetate, 3.3 g (0.026 mol) 1,2-epoxy-5-cyclooctene and a magnetic stir bar. The solution is cooled to 0° C. and sparged with nitrogen for 10 minutes. Grubbs catalyst 848 (1.12 g, 1.31 mmol) is added and the reaction is stirred at 0° C. for 24 hours. The reaction is quenched by addition of 15 ml of 2M THP in IPA solution, warmed to 60° C. with stirring for 24 hours. Water (5 mL) is added and stirred vigorously for 10 minutes. The aqueous layer is separated, and the product washed with brine solution and dried over sodium sulfate. The product is purified by vacuum distillation, and then hydrogenated using 10% palladium on carbon with a 5 psi overpressure of hydrogen. The catalyst is filtered off without further purification. The epoxide is converted to the trans olefin as described in J. Amer. Chem. Soc. 98, 1265 (1976); J. Org. Chem. 41, 3063 (1976); Chem. Commun. 168 (1980)). 11,12-Epoxy-hexadecyl acetate is treated with 3.87 g (0.026 mol) hexamethyldisilane and 3.34 g (0.026 mol) potassium methoxide at room temperature (about 25° C.). The solution is warmed to 50° C. and stirred until the starting materials are consumed. The mixture is quenched with water and the organic phase is washed with 1 M hydrochloric acid, saturated aqueous solution of sodium bicarbonate, and finally brine. The organic phase is dried over sodium sulfate and vacuum distilled to yield E-11-hexadecenyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[Br:11][CH2:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCBr)cc1
Yield: 70.1 %

Procedure:
p-Hydroxyacetophenone (13.6 g.), 1,3-dibromopropane (121.2 g.) and potassium carbonate (15.8 g.) were dissolved in acetone (250 ml.), and the solution was refluxed under heating for 6 hours. After the reaction mixture was filtered, the acetone was removed by evaporation from the filtrate under reduced pressure to give an oily residue. The excess of 1,3-dibromopropane was removed by distillation from the oily residue under reduced pressure to give a residue, which was subjected to column chromatography on silica gel (20 g.). Elution was carried out with benzene and the fractions containing a desired compound were collected. The eluate was evaporated to dryness under reduced pressure to give p-(3-bromopropoxy)acetophenone (18 g.).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([O:18][C:2]2[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:20][CH2:21]1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CN1CCC(Oc2ncccc2OCCO)CC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 64.1 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 4-hydroxy-N-methylpiperidine (67 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 62 mg (0.25 mmol, 63%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 253 (M+1)+, calc. 253 (M+1)+.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[CH2:24])=[N-]>ClCCl>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:24])=[O:18])=[CH:20][CH:21]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)c1ccc(Nc2ccn(-c3ccccc3)n2)cc1

Procedure:
4-(1-Phenyl-1H-pyrazol-3-yl)aminobenzoic acid (0.110 g) in dry dichloromethane was treated with an excess of ethereal diazomethane. After 5 minutes the solvents were evaporated to yield the title compound, mp 160°-161°.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH2:6][S:7]C(=O)C)(=[O:3])[CH3:2].[Cl-].[Na+]>O.N>[C:1]([NH:4][CH:5]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])[CH2:6][SH:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=O)NC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
N,S-Diacetyl-DL-cysteinyl-L-proline (0.3 g) is dissolved in a mixture of water (4 ml) and concentrated ammonia (4 ml) under a blanket of argon. The solution is stored for thirty minutes at room temperature, saturated with sodium chloride and extracted with ethyl acetate and chloroform. The organic layers are pooled and concentrated to dryness in vacuo to obtain N-acetyl-DL-cysteinyl-L-proline, yield 0.1 g, Rf =0.25 (silica gel; benzene:acetic acid, 75:25).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:19][CH:18]=1)=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:15][C:17]1[CH:18]=[CH:19][C:20]([CH:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:21][CH:22]=1)[CH2:7][CH2:6]2
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Reactant: CC(=O)NC(C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)NC(C)c1ccc(CN2CCc3cc(C(F)(F)F)ccc3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 74 mg (0.37 mmol) 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline and 70 mg (0.37 mmol) N-(1-(4-Formylphenyl)ethyl)acetamide (example I) in 2 mL THF are added 63 μl (1.1 mmol) AcOH and the reaction mixture is stirred at r.t. for 10 min. The resulting mixture is cooled to 0° C., 117 mg (0.551 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. After that time, the reaction is quenched by the addition of 200 μL water and purified by HPLC.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:26]2[O:30][C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][N:38](C)[C:39](=O)OC(C)(C)C)=[CH:33][CH:32]=3)=[N:28][N:27]=2)=[N:11][C:12]([C:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[CH2:17][CH:16]=2)=[CH:13][N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[CH2:17][CH:16]=2)=[N:11][C:10]=1[C:26]1[O:30][C:29]([C:31]2[CH:32]=[CH:33][C:34]([CH2:37][NH:38][CH3:39])=[CH:35][CH:36]=2)=[N:28][N:27]=1
Reactant: CCC(=O)NC1CC=C(c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)NC1CC=C(c2cnc(N)c(-c3nnc(-c4ccc(CNC)cc4)o3)n2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-[4-(propanoylamino)cyclohexen-1-yl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (21 mg, 0.03 mmol) in DCM (220 μL) was added TFA (326 mg, 220 μL, 2.9 mmol) and the reaction mixture was stirred for 40 minutes at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMF (1 mL) and purified by Gilson reverse phase HPLC using (5-99% ACN/H2O (5 mM HCl)) to yield N-(4-(5-Amino-6-(5-(4-((methylamino)methyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)cyclohex-3-enyl)propionamide. 1H NMR (400 MHz, MeOD) d 8.41 (s, 1H), 8.31 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H), 6.64 (s, 1H), 4.34 (s, 2H), 4.11-3.98 (m, 1H), 2.81 (s, 4H), 2.63 (d, J=17.8 Hz, 2H), 2.26 (q, J=7.7 Hz, 3H), 2.15-2.04 (m, 1H), 1.78 (dd, J=11.3, 5.0 Hz, 1H), 1.18 (t, J=7.6 Hz, 3H). LC/MS m/z 434.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].[CH2:11](I)[CH3:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([CH:9]=1)[CH2:7][OH:8]
Reactant: CCI
Reactant: OCc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(Br)cc1CO

Procedure:
5-Bromo-2-hydroxybenzylalcohol (5.0 g, 24.6 mmol), ethyl iodide (11.5 g, 73.8 mmol) and K2CO3 (3.4 g, 24.6 mmol) in 50 ml of acetone was stirred at +50° C. overnight. The mixture was filtered and evaporated. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 30:100) to give 5-bromo-2-ethoxybenzyl alcohol.
Reaction SMILES: [N:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:13]([N-:16]C(C)C)(C)[CH3:14].[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.BrCC#N>C1COCC1.C(OCC)(=O)C>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:14][C:13]#[N:16])[CH3:12]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)CN1CCCCC1
Agent: N#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC#N)N1CCCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
Treat a −78° C. solution of ethyl 1-piperidine acetate (20.0 g, 0.117 mol) in THF (200 mL) with a 2M solution of lithium diisopropylamide in heptane/THF/ethylbenzene (70.1 mL, 0.140 mol) and stir at −78° C. for 20 minutes under N2. Treat the reaction with bromoacetonitrile (21.00 g, 0.175 mol) and stir at −78° C. for 15 minutes. Warm the reaction to room temperature and stir 4 hours. Quench the reaction into saturated ammonium chloride. Dilute the reaction with ethyl acetate and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 0 to 20% ethyl acetate in hexanes gradient to afford 6.74 g (27%) of the titled product. Rf=0.41 (3/1 hexanes/ethyl acetate). ES MS (m/z): 211 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11](Cl)[C:12](Cl)=[C:13](Cl)[C:14]=1Cl)[C:8]([OH:10])=[O:9].[CH2:20]([SH:30])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([S:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:12]([S:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:13]([S:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:14]=1[S:30][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:8]([OH:10])=[O:9]
Reactant: CCCCCCCCCCS
Reactant: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(O)=NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCSc1c(SCCCCCCCCCC)c(SCCCCCCCCCC)c(C(O)=NCCO)c(C(=O)O)c1SCCCCCCCCCC

Procedure:
2 g (6.08 millimols) of tetrachlorophthalic acid N-2-hydroxyethylimide, 5.30 g (30.4 millimols) of n-decanthiol, 6.30 g (45.6 millimols) of potassium carbonate and 20 ml of N,N-dimethylformamide are stirred at 25° C. for 7 hours. The mixture is acidified and extracted with methylene chloride. After recrystallisation from n-hexane at 0° C., 3.75 g (70% of theory) of the title compound are obtained; melting point 57°-8° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C@H:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OCC3C=CC=CC=3)[CH2:12]2)=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C@H:11]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCO[C@H]2CC[C@H](NC(=O)OCc3ccccc3)C2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(CCO[C@H]2CC[C@H](N)C2)cc1
Yield: 85.3 %

Procedure:
A mixture of benzyl {trans-3-[2-(4-methylphenyl)ethoxy]cyclopentyl}carbamate (291 mg, 0.82 g) and 5% palladium on carbon (150 mg) in ethanol (8 ml) was hydrogenated (hydrogen balloon) for three hours. The catalyst was removed by filtration through Celite. The filter cake was washed with ethanol (3×10 ml) and the filtrate was concentrated under reduced pressure to give an oil. The oil was filtered through a pad of silica gel eluting first with methanol: methylene chloride (10:90) to remove impurities, then with methanol: methylene chloride: conc. ammonium hydroxide (20:80:2), and the filtrate concentrated to give trans-3-[2-(4-methylphenyl)ethoxy]cyclopentanamine (154 mg, 86%), as a colorless oil.