Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[CH3:4][CH:5]1[N:10]([CH2:11][C:12]2[C:20]3[O:19][CH:18]=[CH:17][C:16]=3[CH:15]=[C:14]([N+:21]([O-])=O)[CH:13]=2)[CH2:9][CH2:8][N:7]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:6]1>[Ni].C(O)C.C1COCC1>[NH2:21][C:14]1[CH:13]=[C:12]([CH2:11][N:10]2[CH2:9][CH2:8][N:7]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:6][CH:5]2[CH3:4])[C:20]2[O:19][CH:18]=[CH:17][C:16]=2[CH:15]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cc([N+](=O)[O-])cc2ccoc12
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(N)cc2ccoc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 127 %

Procedure:
Raney nickel (slurry in ethanol) and hydrazine hydrate (97 μL, 2.0 mmol) were added to tert-butyl 3-methyl-4-[(5-nitro-1-benzofuran-7-yl)methyl]piperazine-1-carboxylate (115 mg, 0.31 mmol; obtained in Step 1) in ethanol:THF (4:1; 5 mL). The resulting mixture was stirred at room temperature for 1.5 h, followed by filtration through Celite. The Celite pad was rinsed several times with ethanol. The solvent was evaporated to give the crude product (136 mg) as a light green solid. This material was used in the next step without further purification. HPLC 98%, RT=1.77 min (System A; 5-60% MeCN over 3 min), 100%, RT=1.50 min (System B; 5-60% MeCN over 3 min). MS (ESI+) for C19H27N3O3 m/z 346 (M+H)+.
Reaction SMILES: CC(O)=O.CCO.[Br:8][C:9]1[CH:10]=[C:11]([O:18][C@@H:19]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=2[Cl:29])[CH3:20])[C:12]([N+:15]([O-])=O)=[N:13][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].O.C(OCC)C>[Br:8][C:9]1[CH:10]=[C:11]([O:18][C@@H:19]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=2[Cl:29])[CH3:20])[C:12]([NH2:15])=[N:13][CH:14]=1
Reactant: C[C@@H](Oc1cc(Br)cnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOCC
Product: C[C@@H](Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a stirred mixture of AcOH (150 mL) and EtOH (150 mL) was suspended 5-bromo-3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-2-nitropyridine (6.6 g, 0.016 mol) and iron chips (8.8 g, 0.16 mol). The reaction was heated slowly to reflux and allowed to stir for 1 hour. The reaction was cooled to room temperature then diethyl ether (100 mL) and water (100 mL) was added. The solution was carefully neutralized by the addition of sodium carbonate. The combined organic extracts were washed with saturated NaHCO3 (2×100 mL), H2O (2×100 mL) and brine (1×100 mL) then dried over Na2SO4, filtered and concentrated to dryness under vacuum to yield the title compound as a white solid (5.0 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH:12](OCCCC)=O.C(N(CC)CC)C.O=P(Cl)(Cl)Cl>C1COCC1>[N+:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2)#[C-:12]
Reactant: Nc1ccc2c(c1)CCC2=O
Reactant: CCCCOC=O
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: [C-]#[N+]c1ccc2c(c1)CCC2=O
Reaction time: 2 h

Procedure:
A mixture of 5-amino-2,3-dihydroinden-1-one (5) and butyl formate (5 eq.) was allowed to reflux overnight. The reaction mixture was then concentrated to an oil which solidified upon standing. The crude material [N-(1-oxo-2,3-dihydro-1H-inden-5-yl)formamide (15.00 g, 73 mmol)] was suspended in cold (0° C.) THF (300 mL) and triethylamine (81 mL, 582 mmol). To this was slowly added 6.6 mL (1 eq.) of POCl3. HPLC after 2 hours showed almost complete conversion. The crude reaction mixture was added to silica gel and concentrated (the bath temp was kept at about 25° C.), and the concentrated mixture was loaded onto a silica column. The product was eluted with DCM (100%) to give 5-isocyano-2,3-dihydroinden-1-one (6).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([O-:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20].[K+].CC(C)([O-])C.[K+]>C1COCC1>[F:11][C:12]1[CH:18]=[CH:17][C:15]([O:16][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22]
Reactant: [O-]c1ccc(F)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in anhydrous THF (5 mL) at 0° C., a 1M solution of a potassium 4-fluoro-3-trifluoromethyl-phenoxide (2.2 mmol) in THF (may be generated by adding the corresponding alcohol to a 1M solution of potassium t-butoxide in THF) was added dropwise and under a nitrogen stream, according to General Procedure L1. The reaction mixture was stirred at 0° C. until completion, as indicated by TLC or HPLC. The solvent was then removed in vacuuo and the reaction mixture was treated with cold H2O (15 mL), and extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of the solvent in vacuuo afforded the desired 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude product could be used directly for further transformation .
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][C:20]=1[O:27][CH3:28].C(N(CC)CC)C.C(OCC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([OH:18])=[C:20]([O:27][CH3:28])[CH:21]=1
Reactant: COc1cc(CN)ccc1O
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
An amount of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.3 g, 1.06 mmol) in N,N′-dimethylformamide is added to 0.2 g (1.06 mmol) of 4-hydroxyl-3-methoxybenzylamine hydrochloride, and 0.22 mL (2.12 mmol) of triethylamine. The reaction mixture is stirred at room temperature under N2 for 2 h. Diethyl ether is added and the resulting tan precipitate is collected and washed successively with methanol, ether, and hexane to yield 0.28 g (65.1% yield) of light yellow solid: mp 260-261° C.; 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.69 (m, 1H), 9.02 (bs, 1H), 8.71 (d, J=9 Hz, 1H), 8.10 (s, 1H), 7.87 (d, J=9 Hz, 1H), 7.30 (d, J=6 Hz, 1H), 7.02 (s, 1H), 6.78 (m, 2H), 4.60 (d, J=4.8 Hz, 2H), 3.78 (s, 3H); MS (ESI) m/z 403.1 (M−H)−1, Analysis for C18H15BrN2O4.(0.33H2O), Calcd: C, 52.98; H, 3.76; N, 6.96. Found: C, 52.83; H, 3.86; N, 6.85.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[F:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([S:22]([NH:13][C:11]2[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[C:10]=2[N:9]=[CH:8][CH:7]=[CH:6]3)(=[O:23])=[O:24])=[C:15]([F:14])[CH:20]=1
Reactant: COc1cc(N)c2ncccc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1F
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2F)c2ncccc2c1
Yield: 54.5 %

Procedure:
In a similar fashion using route 14 general procedure 26, 6-methoxyquinolin-8-amine (Intermediate 23) (60 mg, 0.35 mmol), 2-fluoro-4-chlorobenzenesulfonyl chloride (100 mg, 0.45 mmol) gave the title compound (70 mg, 56%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:27][CH3:28])=[C:12]([C:14]([CH3:26])([CH3:25])[CH2:15][C@:16]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:17](O)=[O:18])[CH:13]=1>O1CCCC1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:27][CH3:28])=[C:12]([C:14]([CH3:26])([CH3:25])[CH2:15][C@@:16]([C:20]([F:22])([F:23])[F:21])([OH:24])[CH2:17][OH:18])[CH:13]=1
Reactant: COc1ccc(F)cc1C(C)(C)C[C@@](O)(C(=O)O)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CO)C(F)(F)F
Temperature: 50 °C
Reaction time: 13 h
Yield: 44.5 %

Procedure:
A solution of lithium aluminium hydride (1M in tetrahydrofuran, 12.6 mL, 12.6 mmol) was introduced into a flask under a nitrogen atmosphere. The solution was heated to 50° C. under nitrogen. (2R)-4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanoic acid (2 g, 6.17 mmol) in tetrahydrofuran (4 mL) was then added dropwise using a syringe pump (50 mL/h addition rate). The solution was then stirred for 13 h at 50° C. The reaction mixture was then cooled to 0° C. and quenched with a slow addition (10 mL/h addition rate) of water (0.5 mL) keeping the temperature below 5 C. Once gas evolution stopped, the cloudy solution was allowed to warm to 20° C. and 15% aqueous sodium hydroxide solution (0.5 mL) followed by water (1.5 mL) were added dropwise (40 mL/h addition rate). The slurry was stirred for 15 min at room temperature, filtered and the inorganic salts were washed twice with ethyl acetate (2×10 mL). The organic liquors were then washed successively with 7.5% aqueous sodium bicarbonate solution (20 mL) and saturated brine (20 mL). The organic liquor was split into two equal amounts, the first half was concentrated to dryness to afford the title compound (851 mg) and the second half was re-crystallised from methyl-cyclohexane to afford the title compound (595 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].C([O-])(O)=O.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19](Cl)=[O:20]>C(#N)C.O>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19]([NH:1][C:2]1[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[OH:8])=[O:20]
Reactant: O=C(Cl)c1ccc(Cl)c(Br)c1
Reactant: Cc1cccc(O)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(O)c1NC(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
2-Amino-m-cresol (4.9 g, 40 mmol) was dissolved in a mixture of acetonitrile (90 mL) and water (80 mL) containing NaHCO3 (6.7 g, 80 mmol) with vigorous stirring. 3-Bromo-4-chloro-benzoyl chloride (10.1 g, 40 mmol, Step 2A) was added in several portions and the mixture was stirred at room temperature for 3 hrs. The resulting precipitates were filtered, washed with water and tert-butyl methyl ether, then dried to yield 3-bromo-4-chloro-N-(2-hydroxy-6-methyl-phenyl)-benzamide (11.3 g). MS (M+H)+: 339.7/341.7; tR=2.36 min. (method 1)
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([NH:15][C@@H:16]([CH2:23][O:24][CH2:25][CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O)(C)(C)C>>[ClH:1].[CH2:25]([O:24][CH2:23][C@H:16]([NH2:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:26]
Reactant: CCOC[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC[C@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.5 ml of 4N-HCl/dioxane solution were added to 0.66 g (2.5 mmols) of N-t-butoxycarbonyl-(R)-α-ethoxymethylbenzylamine, and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, 30 ml of ether was added to the residue, and this was further concentrated to obtain (R)-α-ethoxymethylbenzylamine hydrochloride at a quantitative yield.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]1)=O>>[CH2:49]([N:46]1[CH2:47][CH2:48][N:43]([CH2:41][CH2:40][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:37][CH:38]=2)[CH2:44][CH2:45]1)[CH3:50]
Reactant: CCN1CCN(C(=O)CCl)CC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Product: CCN1CCN(CCOc2ccc(CN(c3cc(OC)ccc3C3CCc4cc(O)ccc4C3)C(C)C)cc2)CC1
Yield: 52.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-1-(4-ethylpiperazin-1-yl)ethanone (16 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([N+:19]([O-])=O)=[CH:13][CH:12]=3)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([NH2:19])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)cc12
Yield: 78.6 %

Procedure:
A suspension of Pd (10% on carbon, 1.0 g), and Compound 15 (8.0 g, 28 mmol) in anhydrous ethanol (300 mL) was hydrogenated (2280 mL) at 1 atm. The reaction mixture was filtered through a filter aid. The filtrate was concentrated in vacuo to give the title compound (5.62 g, 79%). M.p. 226°-228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([N:15]=[C:16]=[O:17])[CH:13]=[CH2:14].C(OCC)C>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:16]([NH:15][CH2:12][CH:13]=[CH2:14])=[O:17])=[O:7])=[CH:4][CH:3]=1
Reactant: C=CCN=C=O
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
At 50° C., 5.00 g (29.3 mmol) of 4-chlorobenzohydrazide were suspended in 150 ml of dry THF. 2.63 ml (29.9 mmol) of allyl isocyanate, dissolved in 110 ml of dry THF, were then added dropwise. Initially, all of the starting material dissolved, and then a fine precipitate formed. The mixture was stirred at 50° C. for 2 h. After cooling to room temperature, diethyl ether was added. The colorless solid was filtered off with suction, washed with diethyl ether and dried under high vacuum. This gave 7.42 g (100% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CCCCCC>O1CCCC1>[F:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](=[O:14])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 4-methylpyridine (74.4 g) and ethyl 4-fluorobenzoate (134.4 g) in dry tetrahydrofuran (600 ml) was added a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.6 l) dropwise with ice cooling. The mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture was added hexane (2.2 l) and the separated solid was collected, washed with hexane and dried. The obtained solid was dissolved in 3N-hydrochloric acid (800 ml) and the solution was neutralized with an aqueous saturated sodium bicarbonate solution. The separated solid was collected, washed with water and dried to give 1-(4-fluorophenyl)-2-(pyridin-4-yl)ethan-1-one (148 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([C:25]([O:27]CC2C=CC=CC=2)=[O:26])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].C(O)(=O)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]([C:11]1([C:25]([OH:27])=[O:26])[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:22])[Cl:23])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCCC(C(=O)OCc2ccccc2)(C(=O)OCc2ccccc2)C1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)N1CCCC(C(=O)O)(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3,3-dibenzyl ester (5.5 g 15 mmol) in N,N-dimethylformamide (200 mL) cooled with a water/ice bath, is added potassium hydroxyde (0.9 g 85% 14 mmol) dissolved in water (40 mL). The mixture is stirred with cooling for 2 h, allowed to warm to room temperature, acidified with acetic acid (1.05 ew) and concentrated under reduced pressure. Addition of water cristallizes the crude which is filtered, dissolved in ethyl acetate, washed with water, dried over magnesium sulphate and concentrated under reduced pressure. Cristallisation with heptane affords piperidine-1,3,3-tricarboxylic acid 1-(2,2,2-trichloroethyl) 3-benzyl ester.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@H:8]([CH3:19])[O:7][C@H:6]1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31])(=O)C.C[O-].[Na+]>CO>[C@@H:6]1([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=2)[C:30]([O:32][CH3:33])=[O:31])[O:7][C@@H:8]([CH3:19])[C@@H:9]([OH:15])[C@@H:10]([OH:11])[C@@H:5]1[OH:4]
Reactant: COC(=O)c1cccc(-c2ccccc2O[C@@H]2O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(-c2ccccc2O[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
Part E: Methyl 3-(2-(2,3,4-tri-O acetyl-α-L-fucopyranosyloxy)phenyl)benzoate (1.08 g, 1.45 mmol) was dissolved in methanol (25 ml) in a 50 ml flask, then treated with sodium methoxide (100 mg) and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was flushed through silica gel with 7:3 methylene chloride/methanol which provided methyl 3-(2-(α-L-fucopyranosyloxy)phenyl)benzoate (0.48 g, 59%) as a white solid, m.p.: 137°-140° C.; 1H NMR (300 MHz, CDCl3): 8.27 (s, 1H), 8.00 (d, J=8, 1H), 7.75 (d, J=8, 1H), 7.51 (t, J=8, 1H), 7.32-7.44 (comp, 3H), 7.10-7.20 (comp, 1H), 5.54 (d, J=2.7, 1H), 3.94 (s, 3H), 3.60-4.10 (comp, 7H), 1.26 (d, J=6, 3H); IR (KBr): 3421, 2938, 1718, 1437, 1245, 1083, 1035, 964, 844, 763; analysis: calculated for C20H22O7.0.25[H2O]: 63.4% C; 6.0% H. found: 63.3% C; 5.9% H.
Reaction SMILES: [CH2:1]([C:3]1([CH3:13])[CH:8]([CH3:9])[CH2:7][CH2:6][C:5]([CH2:11][CH3:12])([CH3:10])[NH:4]1)[CH3:2].[C:14](Cl)(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:14]([N:4]1[C:5]([CH2:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH:8]([CH3:9])[C:3]1([CH2:1][CH3:2])[CH3:13])(=[O:17])[CH:15]=[CH2:16]
Reactant: CCC1(C)CCC(C)C(C)(CC)N1
Reactant: C=CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)N1C(C)(CC)CCC(C)C1(C)CC
Reaction time: 18 h

Procedure:
36.7 g of 2,6-diethyl-2,3,6-trimethylpiperidine (Compound No. 1) are dissolved in 200 ml toluene. A solution of 19 g acrylic chloride in 50 ml toluene is added slowly within an hour and the mixture is stirred at 70°-75° C. for 18 hours. After addition of 21.2 g of triethylamine the stirring is continued for another 24 hours. After cooling the reaction mixture is washed twice with 100 ml water each. The toluene solution is dried over sodium sulfate and evaporated. The residue is distilled in vacuo and there is obtained the 1-acryloyl-2,6-diethyl-2,3,6-trimethylpiperidine (Compound No. 12) as distillate at 133°-135° C./0.6 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26](OC(C)(C)C)=[O:27])[CH2:21]3)=[O:19])[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.[C:35](O)(C(F)(F)F)=O>O1CCOCC1.CO>[C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:20]([C:18]([NH:17][C@H:13]2[CH2:14][CH2:15][CH2:16][N:11]([S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[CH3:33])(=[O:9])=[O:10])[CH2:12]2)=[O:19])[CH2:21]1)(=[O:27])[CH3:35]
Reactant: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](NC(=O)[C@H]2CCCN(C(=O)OC(C)(C)C)C2)C1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)N1CCC[C@H](C(=O)N[C@H]2CCCN(S(=O)(=O)c3cccc(Cl)c3C)C2)C1

Procedure:
tert-Butyl (3S)-3-[((3S)-1-[(3-chloro-2-methylphenyl)sulfonyl]piperidin-3-ylamino)-carbonyl]piperidine-1-carboxylate (10.0 mg, 200 μmol) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (0.5 mL) at rt for 1 h. The volatiles were removed in-vacuo and the residue was dissolved in acetonitrile (0.8 mL) and was treated with diisopropylethylamine (20.0 μL) and acetyl chloride (5.0 μL). The crude reaction mixture was diluted with MeOH (1.3 mL) and was adjusted to a pH of 2 using TFA and was purified by prep-HPLC to give the desired product. LCMS: (M+H)+=442.1/444.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][C@@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:11][C@@H:12]1[CH2:17][N:16]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14][N:13]1[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])nc2)CCN1C(=O)OC(C)(C)C
Temperature: 65 °C
Yield: 49.4 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with methylsulfinylmethane (50 mL), 5-bromo-2-nitropyridine (2.2 g, 11 mmol), (R)-tert-butyl 2-methylpiperazine-1-carboxylate (2.2 g, 11 mmol), and potassium carbonate (3.08 g, 22 mmol). See FIG. 8. The system was subjected to three cycles of vacuum/nitrogen flush and heated at 65° C. for 15 h. It was then cooled to room temperature, and partitioned between ethyl acetate (100 mL) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL×2). The combined organic layer was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column chromatography eluting with 2:1 (UV) petroleum/ethyl acetate to afford 108a as a yellow solid (1.75 g, 50%). LCMS: [M+H]+ 323
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[CH:8][C:9](=[O:11])[CH3:10]>[Pd].C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)C=Cc1cccn1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCc1cccn1C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A mixture of 4-(1-Methyl-2-pyrryl)-but-3-en-2-one (2.98 g) and 10% palladium on charcoal (0.2 g) was hydrogenated in ethyl acetate (50 ml) at room temperature and atmospheric pressure. The catalyst was removed by filtration the solvent evaporated, and the resulting oil left overnight to solidify in a refrigerator. The long, colourless needles which formed were washed with cold 60°-80° petrol to give 4-(1-Methyl-2-pyrryl)-butan-2-one (2.46 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[NH:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH3:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=2)[CH3:12])[C:23]2[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NC(C)c2cccc(C(F)(F)F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(NC(C)c2cccc(C(F)(F)F)c2)c2cccc(N)c2)cc1
Yield: 98.1 %

Procedure:
Following a similar procedure to that described in Example (1b), 2.85 g of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[1-(3-trifluoromethylphenyl)ethyl]amine [prepared as described in step (a) above], 3.15 g of nickel chloride hexahydrate and 1.05 g of sodium borohydride were reacted, to obtain 2.60 g of the title compound as a yellow oil.