Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([NH:19][CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[N+:16]([O-])=O.C(O)C.[ClH:24]>[Fe].O>[ClH:15].[ClH:24].[NH2:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH2:8][CH:7]([C:6]1[CH:5]=[CH:4][S:3][C:2]=1[CH3:1])[NH:19][CH3:20]
Reactant: CNC(Cc1ccc(Cl)cc1[N+](=O)[O-])c1ccsc1C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNC(Cc1ccc(Cl)cc1N)c1ccsc1C

Procedure:
A mixture of 5.00 g of α-(2-methyl-3-thienyl)-N-methyl-4-chloro-2-nitrobenzeneethanamine, 9.32 g of iron powder, 100 ml of 95% ethanol, 25 ml of water, and 0.7 ml of concentrated hydrochloric acid was heated at reflux for 1.5 hr. The mixture was filtered through celite, and the organic phase was evaporated. The residue was basified with 10% aqueous sodium hydroxide, and extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in methanol and acidified with ethereal hydrogen chloride. The solution was diluted with ether, and the solid was collected, washed with ether, dried in vacuo, and recrystallized from methanol/ether to give 2.6 g of product, mp 242°-243° C. (dec.)
Reaction SMILES: [CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([O:22]CC)=[O:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:25]3[CH:31]=[C:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=[CH:28][C:26]=3[N:27]=[C:5]12)([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[CH:1]([CH:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([C:20]([OH:22])=[O:21])=[CH:12][N:11]=2)[CH2:8][CH2:7][N:6]2[C:25]3[CH:31]=[C:30]([S:32]([CH3:35])(=[O:33])=[O:34])[CH:29]=[CH:28][C:26]=3[N:27]=[C:5]12)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(N2CCn3c(nc4ccc(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1c1ncc(C(=O)O)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.4 %

Procedure:
To a solution of ethyl 2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (20 mg, 0.04 mmol, prepared according to example 3) in MeOH (3 mL), H2O (1 mL) was added NaOH (4.7 mg, 0.12 mmol). The mixture was stirred at rt overnight. The mixture was diluted with water (10 mL), acidified with 1N HCl to pH=3-4 and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (20 mg, 100% yield) as a yellow solid, which was used for the next step without further purification.
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:16][C:17]([O-])([CH3:19])[CH3:18].[K+].[I-].[Na+]>C(O)(C)(C)C>[CH2:16]([O:4][CH2:3][CH2:2][CH:2]([C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:17]1[CH:19]=[CH:8][CH:6]=[CH:7][CH:18]=1
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)C(CCOCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 48 h

Procedure:
Di(tert-butyl) malonate (151.4 g, 686 mmol) was added dropwise at 50° C. to a suspension of potassium tert-butylate (77 g, 686 mmol) in 500 ml of tert-butanol. Sodium iodide (10.33 g) was then added, followed by dropwise addition of Intermediate 5C (117.1 g, 686 mmol) at 40-50° C. The resulting thick suspension was stirred at 70° C. for two days. During this time, two further portions of potassium tert-butylate (15.4 g each, 70 mmol) were added. The mixture was then poured into ice-water and extracted three times with diethyl ether. The organic layers were dried over Na2SO4, filtered and evaporated. The crude product was finally purified by column chromatography using a cyclohexane/ethyl acetate gradient (70:1→15:1).
Reaction SMILES: [CH2:1]([Si:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH:14]=[CH:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:25][C:26]1[CH:31]=[CH:30][C:29]([Li])=[CH:28][CH:27]=1>>[CH2:1]([Si:6]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10][CH:9]([C:12]2[CH2:17][CH2:16][C:15]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C2C=CC(=O)CC2)CC1
Reactant: [Li]c1ccc(F)cc1
Product: CCCCC[Si]1(c2ccccc2)CCC(C2=CC=C(c3ccc(F)cc3)CC2)CC1
Yield: 74 %

Procedure:
In the same manner as in Example 1, 50.0 g of 4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)-2-cyclohexenone was subjected to coupling reaction with 4-fluorophenyllithium, followed by dehydration reaction in the presence of an acid catalyst to obtain 45.5 g of 1-(4-n-pentyl-4-phenyl-4-silacyclohexyl)-4-(4-fluorophenyl)-1,3-cyclohexadiene (yield: 74%). The results of IR analysis of the compound are shown below.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33]([N:35]=[N+]=[N-])[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2].C(Cl)Cl.CO>C1COCC1.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33]([NH2:35])[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(N=[N+]=[N-])ncn5)ccc43)cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(N)ncn5)ccc43)cc2)CC1

Procedure:
Hydrogenation of 0.38 mMol 5-(6-azido-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid [4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-amide in 10 ml THF in the presence of 70 mg Pd/C 10%, filtration, concentration of the filtrate, chromatography (Combi Flash; CH2Cl2/MeOH/NH3conc. 98:2:0→90:10:1) and crystallization from DIPE gives the title compound: MS: [M+1]+=474; TLC(EtOAc/EtOH/NH3conc. 80:20:1): Rf=0.09; Anal.: C,H,N.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:17]=[C:16]([C:18](=[O:40])[NH:19][CH2:20][C:21](=[O:39])[N:22]3[CH2:27][CH2:26][CH:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=4)[CH2:24][CH2:23]3)[NH:15][N:14]=2)[CH:8]=1.C(C1C=C(C=CC=1)C(OC)=O)(=O)C.N1C=CC=N1>C1COCC1.CO.O>[O:39]=[C:21]([N:22]1[CH2:23][CH2:24][CH:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)[CH2:26][CH2:27]1)[CH2:20][NH:19][C:18]([C:16]1[CH:17]=[C:13]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:41])=[O:5])[NH:14][N:15]=1)=[O:40]
Reactant: COC(=O)c1cccc(-c2cc(C(=O)NCC(=O)N3CCC(Oc4cccc(C(F)(F)F)c4)CC3)[nH]n2)c1
Agent: COC(=O)c1cccc(C(C)=O)c1
Agent: [Li]O
Agent: c1cn[nH]c1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(-c2cc(C(=O)NCC(=O)N3CCC(Oc4cccc(C(F)(F)F)c4)CC3)n[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
LiOH.H2O (32 mg, 0.76 mmol) was added to a stirred mixture of 3-(5-{2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethylcarbamoyl}-1H-pyrazol-3-yl)-benzoic acid methyl ester (99 mg, 0.2 mmol) (prepared by the method used for the synthesis of Example 102, starting, alternatively from methyl 3-acetylbenzoate to generate the 1H-pyrazole intermediate) in THF:MeOH:H2O (3:2:1, 38 mL) was added, and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure Cold water was then added and the contents were acidified with 10% aqueous HCl, the precipitate was filtered. The solid obtained was purified by recrystallisation form methanol to afford 50 mg (38.1% Yield) of 3-(5-{2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethylcarbamoyl}-2H-pyrazol-3-yl)-benzoic acid. LC/MS [M+H]+: 517, 95.29%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 13.2 (s, 1H), 8.38 (s, 1H), 8.04 (d, 1H), 7.9 (d, 1H), 7.5 (m, 2H), 7.26 (t, 3H), 7.18 (bs, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH:3]=[C:4]([CH3:7])[CH:5]=[CH2:6].[CH3:8][CH2:9][C:10](=[O:13])[CH2:11][CH3:12].[OH-].[K+]>CCCCC>[CH3:8][CH:9]([CH2:6][CH:5]=[C:4]([CH3:7])[CH:3]=[CH2:2])[C:10](=[O:13])[CH2:11][CH3:12]
Reactant: C=CC(C)=CCCl
Reactant: CCC(=O)CC
Agent: [K+]
Agent: [OH-]
Solvent: CCCCC
Product: C=CC(C)=CCC(C)C(=O)CC
Yield: 61.7 %

Procedure:
According to the procedure described in Example 1, from 58 g of 1-chloro-3-methyl-2,4-pentadiene and 43 g of pentan-3-one (diethyl ketone) in the presence of 50 g of powdered potassium hydroxide in 200 ml of dry pentane there are obtained 51 g of crude 4,7-dimethyl-6,8-nonadien-3-one which are subjected to a fractional distillation.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[CH:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]4)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH:15]=[CH:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12C=CC(=O)NC1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)C=C[C@]2(C)c3ccc(-c4cccc([N+](=O)[O-])c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
A 15 mL round bottom flask was charged with (+)-4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one (12 mg, 0.034 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (12 mg, 0.10 mmol). Methyl iodide (0.006 mL, 0.10 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 9 mg (75%) of the title compound as a white solid, upon trituration from diethyl ether/hexanes. mp 175°-177°. FDMS: m/e=348.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=3)[C:20]([C:30]([F:33])([F:32])[F:31])=[CH:19][N:18]=2)=[CH:4][C:5]([CH3:15])=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:1][C:2]1[CH:7]=[C:6]([C@H:8]2[CH2:13][CH2:12][C@@H:11]([N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:10][CH2:9]2)[C:5]([CH3:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[C:20]([C:30]([F:33])([F:32])[F:31])=[CH:19][N:18]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c([C@H]4CC[C@@H](N5CCCCC5)CC4)cc3F)ncc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(5-fluoro-2-methyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone (30 mg, 0.065 mmol), piperidine (30 μL, 0.174 mmol) and acetic acid (75 μL, 0.13 mmol) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (27.4 mg, 0.13 mmol) was added to the reaction and the reaction mixture was stirred overnight. The mixture was concentrated and purified by silica chromatography (MeOH/DCM 8:92) to afford N2-(2-fluoro-5-methyl-4-(cis-4-(piperidin-1-yl)cyclohexyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine; Rf: 0.41 (Silica; MeOH/DCM 8:92); ESMS m/z 532.3 (M+H+).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][C@@H:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].Cl[C:17]1[O:18][C:19]2[C:20](=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:24][CH:25]=2)[N:21]=1>COCCOC>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:17]2[O:18][C:19]3[C:20](=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:24][CH:25]=3)[N:21]=2)[C@@H:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: C=CCN1CCN[C@@H](CC(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCN1CCN(c2nc3c(C(=O)OC)cccc3o2)[C@@H](CC(C)C)C1
Reaction time: 0.75 h
Yield: 43 %

Procedure:
To a solution of (S)-1-allyl-3-isobutylpiperazine (442 mg, 2.42 mmol) in DME (10 mL) at room temperature, was added NaH (60% suspension in mineral oil, 100 mg, 2.42 mmol) and the mixture was stirred for 45 min. Methyl 2-chlorobenzoxazole-4-carboxylate (510 mg, 2.42 mmol) was added to the reaction mixture and the reaction was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 10:1:0.1 CH2Cl2/CH3OH/concentrated NH4OH) to afford methyl 2-(4-allyl-(S)-2-isobutylpiperazine-1-yl)benzoxazole-4-carboxylate (372 mg, 43%) as a yellow oil. 1H NMR and MS consistent.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:36][C:37]1([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)[CH:42]2[CH:38]1[CH2:39][NH:40][CH2:41]2.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:36][C:37]1([C:43]2[CH:44]=[C:45]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:46]=[CH:47][CH:48]=2)[CH:42]2[CH:38]1[CH2:39][N:40]([C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:41]2
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: O=C(O)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
To a solution of 4-phenylbutanoic acid (219 mg, 1.33 mmol) in N,N-dimethylformamide (20 ml) was added 1-hydroxybenzotriazole monohydrate (225 mg, 1.48 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (382 mg, 1.98 mmol). After stirring at room temperature for 15 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 449 mg, 1.48 mmol) and sodium hydrogen carbonate (225 mg, 2.7 mmol). The reaction mixture was stirred at room temperature for overnight before concentrating in vacuo. Water (15 ml) was added and the reaction mixture was extracted with ethyl acetate (20, 15 ml). The combined organic extracts were washed with water (15 ml), dried (MgSO4), filtered and concentrated in vacuo to give a colourless oil (540 mg). This was purified by chromatography using a Biotage Flash 12™ cartridge packed with silica gel (8 g) eluting with hexane:ethyl acetate (100:0 to 0:100 over 30 min) and then with ethyl acetate:methanol (100:0 to 0:100 over 5 min) to afford the title compound as a colourless glass (360 mg, 59%).
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:17]=[C:18]([N:25](CC3C=CC(OC)=CC=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]3[N:20]([CH:22]=[CH:23][N:24]=3)[N:21]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1.CC(O)=O.[H][H].C(O)(C(F)(F)F)=O>[Pd].CO>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:17]=[C:18]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]3[N:20]([CH:22]=[CH:23][N:24]=3)[N:21]=2)[CH2:13][CH2:14]1
Reactant: [H][H]
Reactant: COc1ccc(CN(c2ccccc2)c2cc(CN3CCC(NCc4ccccc4)CC3)nn3ccnc23)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NC1CCN(Cc2cc(Nc3ccccc3)c3nccn3n2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
In a Parr bottle was added 6-((4-(benzylamino)piperidin-1-yl)methyl)-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (0.030 g, 0.056 mmol) from (1e), MeOH (7 ml), Pd/C (0.030 mg, 0.282 μmol) and AcOH (0.020 ml, 0.349 mmol). Added hydrogen to a pressure of 55 psi and let shake overnight. The suspension was filtered through celite and rinsed with MeOH, concentrated, and then diluted with TFA (1 ml). The mixture was allowed to stir at room temperature for 6 hours, concentrated and diluted with MeOH (2 ml) and purified by HPLC (10-75% MeOH/Water) to provide the title compound (0.009 g, 49.6% yield) as a TFA salt. 1H NMR (500 MHz, MeOH) δ ppm 8.08 (1H, d, J=2.75 Hz), 7.76 (1H, d, J=2.75 Hz), 7.47 (2H, dd, J=7.56, 3.44 Hz), 7.40-7.45 (2H, m), 7.25-7.31 (1H, m), 6.78 (1H, d, J=3.67 Hz), 4.40 (2H, d, J=3.21 Hz), 3.74 (2H, d, J=11.00 Hz), 3.46 (1H, d, J=3.67 Hz), 3.22 (2H, t, J=12.14 Hz), 2.25 (2H, d, J=14.20 Hz), 2.00 (2H, m). LC/MS, m/z 323 (M+1). HPLC Rt, 1.04 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [CH3:1][C:2]([CH3:11])=[CH:3][CH2:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][CH:7]=1>C(O)C.[Pd]>[CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][CH:7]=1
Reactant: CC(C)=CCCc1ccsc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CCCc1ccsc1
Reaction time: 72 h
Yield: 66 %

Procedure:
To 12 g of freshly distilled 3-(4-methyl-pent-3-enyl)-thiophene dissolved in 150 ml ethanol was added 1 g of 5% Pd/C hydrogenation catalyst. The mixture was hydrogenated at atmospheric pressure in 72 hours. The catalyst was filtered of, the solvent evaporated and the residue distilled, yielding 8 g (66%) 3-(4-methylpentyl)-thiophene. Boiling point: 65°-66° C./0.13 kPa. nD20 =1.4962.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:3]=1[CH2:4][N:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](=[O:14])[NH:7][C:6]1=[O:15].[C:21]([O:25][C:26](=[O:37])[NH:27][C@H:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:29]O)([CH3:24])([CH3:23])[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:21]([O:25][C:26](=[O:37])[NH:27][C@H:28]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:29][N:7]1[C:8](=[O:14])[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:19][CH:18]=[CH:17][C:16]=2[F:20])[C:6]1=[O:15])([CH3:22])([CH3:23])[CH3:24]
Reactant: O=c1[nH]c(=O)n(Cc2c(F)cccc2F)cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c([N+](=O)[O-])cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
1-(2,6-difluoro-benzyl)-5-nitro-1H-pyrimidine-2,4-dione (82 mg, 0.29 mmol), ((R)-2-hydroxy-1-phenyl-ethyl)-carbamic acid tert-butyl ester (69 mg, 0.29 mmol), and triphenylphosphine (114 mg, 0.44 mmol) were dissolved in anhydrous tetrahydrofuran (2 mL). To this solution was added diethyl azodicarboxylate (200 μl, 0.44 mmol), followed by stirring at room temperature for 4 hrs. The solution was concentrated, after which the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 3/1/1) and dried in a vacuum to afford 67 mg of the compound as a colorless oil (yield 67%). 1H NMR (300 MHz, CDCl3) δ 1.30 (9H, s), 3.40 (1H, d), 4.50 (1H, m), 5.08-5.27 (4H, m), 7.02 (2H, t), 7.26-7.47 (6H, m), 8.78 (1H, s)
Reaction SMILES: [Si]([O:18][C:19]1[CH:56]=[CH:55][C:22]([O:23][CH2:24][C@@H:25]([OH:54])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:53]=[CH:52][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][NH:43][C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:52]=[CH:53][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:54])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:56][CH:55]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)=[O:42])=[CH:50][CH:49]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4ccc(F)cc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(F)cc1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 63.4 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(4-fluorobenzyl)-1-piperidinecarboxamide (0.320, 0.41 mmol) was reacted following Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.141 g, 0.26 mmol).
Reaction SMILES: [Na].N#N.[CH3:4][CH:5]([C:11](OCC)=O)[C:6]([O:8]CC)=[O:7].[O-]CC.[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]C.[OH-].[K+]>C(O)(=O)C.C(O)C>[CH3:4][CH:5]([CH2:11][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]([OH:8])=[O:7]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: CC[O-]
Agent: N#N
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCCCC(C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
Sodium (12.5 g, 0.54 g-atoms) was gradually added in small pieces to absolute ethanol (375 ml) while stirring under an inert (N2) atmosphere until complete solution of the sodium has taken place. Diethyl methylmalonate (95.5 g, 570 mmol) was then added dropwise to the sodium ethoxide solution over 20 minutes and the mixture was heated at reflux for about 15 minutes. After cooling to room temperature, 1-bromooctane (99 g, 512 mmol) was added dropwise over 15 minutes; the mixture was heated at reflux for 2 hours, cooled and neutralized by adding a few drops of glacial acetic acid. About two-thirds of the alcohol was removed by distillation and the residue was washed with 500 ml of water. The organic phase was separated and the aqueous phase extracted with three 50 ml portions of benzene. The organic phase and extracts were combined, washed with water, and dried over anhydrous magnesium sulfate. The residue obtained upon evaporation of the solvent was treated with a solution of 115 g of 86% potassium hydroxide Pellets in 900 ml of reagent ethanol and the mixture heated at reflux, with stirring, for 4 hours. About two-thirds of the solvent was removed by distillation, 750 ml water was added, followed by sufficient (520 ml) 6N sulfuric acid to bring the pH of the solution to 1-2. The organic phase was separated and the aqueous phase was extracted with two portions of ether. The organic phase and extracts were combined, washed with water, then with saturated sodium chloride solution, and finally dried over magnesium sulfate. The residue obtained upon evaporation of the solvent was heated to 180°-190° C. at which temperature decarboxylation occurred smoothly over a period of several minutes. The crude acid was then distilled through a short Vigreux column to give 64 g of product (73% yield), b.p. 143°/5.8 mm (lit. b.p. 137°/4.4 mm), which showed a purity of >99% by GC.