Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[CH:4][CH:3]=1.[CH3:16][CH2:17][O:18][C:19]([N:21]1[C@@H:25]2[CH2:26][C:27]([CH2:29][C@H:22]1[CH2:23][CH2:24]2)=O)=[O:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:48]CCCl>>[Cl:48][C:14]1[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][CH:27]1[CH2:29][CH:22]2[N:21]([C:19]([O:18][CH2:17][CH3:16])=[O:20])[CH:25]([CH2:24][CH2:23]2)[CH2:26]1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Reactant: CCOC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)N1C2CCC1CC(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C2
Temperature: 25 °C
Reaction time: 240 h
Yield: 22 %

Procedure:
To a solution of 2-(4-chlorophenoxy)phenylamine (130 mg, 0.51 mmol), N-(ethoxycarbonyl)-tropinone (201 mg, 1.02 mmol) and acetic acid (153 mg, 2.55 mmol) in DCE (4 ml), was added sodium triacetoxyborohydride (270 mg, 1.28 mmol). The reaction mixture was allowed to stir at room temperature for 10 days. On return, the reaction was quenched with saturated aqueous sodium sodium bicarbonateonate (15 ml) and extracted with ethyl acetate (2×15 ml). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography then proceeded (eluent; 9:1 hexane:ethyl acetate to ethyl acetate) to afford the title compound as a pale yellow oil (49.7 mg, 22%). 1H NMR (270 MHz, CDCl3): δ 1.24 (3H, t, J=7.2 Hz, CH3), 1.63-1.86 (6H, m, 2×CH2, 2×CH), 2.03-2.18 (2H, m, 2×CH), 3.69-3.72 (1H, m, CH), 4.05-4.30 (3H, m, CH2, NH), 4.39 (1H, d, J=4.5 Hz, CH), 6.57-6.68 (2H, m, Ar—H), 6.77 (1H, d, J=8.9 Hz, Ar—H), 6.82-6.86 (1H, dd, J=1.5, 7.9 Hz, Ar—H), 7.04-7.07 (1H, d, J=1.5, 7.5 Hz, Ar—H), 7.09-7.13 (1H, dd, J=2.2, 8.8 Hz, Ar—H), 7.44-7.45 ppm (1H, d, J=2.5 Hz, Ar—H). 13C NMR (67.93 MHz, CDCl3): δ 14.9, 28.0, 28.3, 35.0, 35.6, 44.5, 52.4, 61.0, 111.5, 116.8, 118.1, 120.1, 125.9, 128.0, 130.3, 132.0, 138.9, 142.0, 152.0, 153.9 ppm. LCMS: M+H, 435.44 HPLC: 95.62% (5.044 min, isocratic 90% acetonitrile, 10% water at 1 ml/min).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]1([C@H:15]2[O:22][CH2:21][C@H:20]3[N:16]2[C:17](=[O:23])[CH:18]=[CH:19]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CS(C)=O.CC(OC)(C)C>[C:9]1([C@H:15]2[O:22][CH2:21][C@H:20]3[N:16]2[C:17](=[O:23])[C@@H:18]2[CH2:4][C@@H:19]23)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[S+](C)(C)=O
Reactant: O=C1C=C[C@H]2CO[C@H](c3ccccc3)N12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: O=C1[C@@H]2C[C@@H]2[C@H]2CO[C@H](c3ccccc3)N12
Reaction time: 0.5 h

Procedure:
At RT NaH (oil free, 12.5 mmol) is added to DMSO (15 mL). The mixture is treated portionwise with trimethylsulfoxonium iodide (12.7 mmol) and stirred for 30 min. A solution of (2R,5S)-2-Phenyl-3-oxa-1-azabicyclo[3.3.0]oct-6-en-8-on (4.97 mmol, J. Org. Chem. 1999, 64, 547-555) in DMSO (3.0 mL) is added and the mixture is stirred for 16 h. After cooling to 4° C. water and TBME (100 mL) are added, the layers are separated and the aq. layer is extracted with TBME (100 mL). The combined organic layers are concentrated in vacuo and the residue is purified by FC (heptane/EtOAc 1/1) to give the desired product as a pale yellow oil. LC-MS (basic): tR=0.77 min; [M+H]+=216.3.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[H][H].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.O>[CH2:15]([O:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(C=O)c1O
Reactant: BrCc1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C=O)c1OCc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
A solution of 2-hydroxy-3-methylbenzaldehyde 20.0 g (147 mmol) prepared by the above 1-(1) in dimethylformamide (DMF) (100 ml) was added to the suspension of sodium hydride 6.5 g (163 mmol) with purity 60% and DMF (40 ml) under ice-cooling. After completion of emission of hydrogen gas, benzyl bromide 25.0 g (147 mmol) was dropped to it in a ice bath. The reaction mixture was stirred for 4 hours at 20° C. After the disappearance of the raw material, water was added to the reaction mixture and it was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed in vacuo and the residue was purified by silica gel chromatography (n-hexane-ethyl acetate) to give 2-benzyloxy-3-methylbenzaldehyde 29.9 g (yield: 91%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)(O)=[O:2].O1CCCC1.C(Cl)(=O)C([Cl:20])=O>>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([Cl:20])=[O:2])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 2.5 °C

Procedure:
To a thin suspension of 4-carboxybenzaldehyde (600 g, 3.92 mol) in tetrahydrofuran (2664 g, 36.57 mol) was added dimethylformadehyde (11.48 g, 0.16 mol) and the reaction mixture was cooled to 0-5° C. with an ice bath. The reaction mixture was then stirred at 0° C. while oxalyl chloride (608.69 g, 4.70 mol) was added slowly. The reaction mixture was stirred until it was deemed complete by 1HNMR to yield the title compound. The reaction mixture was used in the next step without further manipulation.
Reaction SMILES: Cl.Cl[CH:3]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4]1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>O>[N:12]1([CH:3]2[C:11]3[N:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH2:5][CH2:4]2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: ClC1CCc2cccnc21
Agent: Cl
Solvent: O
Product: c1cnc2c(c1)CCC2N1CCCC1
Temperature: 25 °C

Procedure:
5 g of 7-chloro-6,7-dihydro-5H-1-pyrindine hydrochloride were dissolved in 10 ml of water and 8.8 ml of pyrrolidine were added, followed by stirring for two-and-a-half hours at ambient temperature. Extraction was done with methylene chloride and the extracts were washed with water, dried and concentrated to dryness under reduced pressure. The residue was taken up in ethyl acetate, treated with active charcoal, filtered and taken to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of ethyl acetate and triethylamine (95-5) to obtain 4.71 g of the expected product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].ClC(OC)=O.[BH4-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1ccncc1Br
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccncc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a mixture of 3-bromoisonicotinic acid (2.5 g, 12.37 mmol, 1 eq.) and TEA (3.44 mL, 24.75 mmol, 2.0 eq.) in THF (100 mL) was added methyl chloroformate (1.2 mL, 14.85 mmol, 1.2 eq.) at 0° C. The mixture was stirred at 0° C. for 10 min and filtered. To this filtrate was added a suspension of NaBH4 (0.95 g, 24.75 mmol, 2 eq.) in water (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 1 h, quenched with NH4Cl(aq) solution, extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give (3-bromopyridin-4-yl)methanol (1.2 g, 52%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 8.37 (d, J=4.9 Hz, 1H), 7.37 (d, J=4.9 Hz, 1H), 4.61 (d, J=5.5 Hz, 2H), 2.3 (t, J=5.5 Hz, 1H). LRMS (M+H+) m/z 188.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH:18](C(OCC)=O)[C:17](=[O:24])[NH:16][C:15]2=[O:25])[C:7]1=[O:26].C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:18][C:17](=[O:24])[NH:16][C:15]2=[O:25])[C:7]1=[O:26]
Reactant: CCOC(=O)C1C(=O)NC(=O)C12C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Yield: 33.4 %

Procedure:
A mixture of 1'-(3,4-dichlorobenzyl)-4-ethoxycarbonyl-spiro[pyrrolidine-3,3'-indoline]-2,2'5-trione(8.2 g.) and acetic acid (50 ml.) was heated under reflux for 22 hours. The solution obtained was cooled and poured into water (300 ml.). The solid which formed was collected by filtration and recrystallised from methanol to give 1'-(3,4-dichlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2'5-trione (2.3 g.), m.p. 203°-204° C.
Reaction SMILES: [C:1]([C:3]([CH3:16])([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10])[CH3:4])#[N:2].O1CCCC1.[OH-].[Na+].Cl>CO>[C:1]([C:3]([CH3:16])([O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10])[CH3:4])#[N:2]
Reactant: COC(=O)c1cccc(OC(C)(C)C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C#N)Oc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of methyl 3-(1-cyano-1-methylethoxy)benzoate (2.07 g, 9.44 mmol) in methanol (12 ml)/tetrahydrofuran (4 mL) was added 2N aqueous sodium hydroxide solution (9.44 mL, 18.9 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with 6N hydrochloric acid (5 mL), 1N hydrochloric acid (50 mL) was added, and the mixture was extracted with ethyl acetate (50 ml, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=10/90→50/50), and a fraction containing the object product was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and n-hexane to give the title compound (1.01 g, 51%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([O:13][CH2:14]C)=[O:12].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH:10]([CH3:16])[C:11]([O:13][CH3:14])=[O:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1ccc(C)cc1OC
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(C)cc1OC
Reaction time: 1 h

Procedure:
The resulting ethyl 2-methoxy-4-methylphenylacetate was dissolved in tetrahydrofuran (50 ml), and to the solution was added dropwise a 1.0 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (19 ml) at −70° C., the mixture was stirred at the same temperature for 1 hour, then methyl iodide (3.1 ml) was added dropwise to the mixture, and the mixture was further stirred at −30° C. for 1 hour. The reaction mixture was quenched with 2 M aqueous hydrochloric acid (15 ml), and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give methyl 2-(2-methoxy-4-methylphenyl)propionate (2.65 g).
Reaction SMILES: S(O)(=O)(=O)C.[O:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18](C3C=CC(CC(NCC4C=CC=CC=4)=O)=NC=3)=[CH:17][CH:16]=2)[CH2:8][CH2:7]1.ClCCN1CCOCC1.[Br:47]C1C=CC(O)=CC=1>>[Br:47][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][N:9]2[CH2:10][CH2:11][O:6][CH2:7][CH2:8]2)=[CH:16][CH:17]=1
Reactant: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: CS(=O)(=O)O
Agent: ClCCN1CCOCC1
Product: Brc1ccc(OCCN2CCOCC2)cc1

Procedure:
In another aspect the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide mesylate comprising the steps of: (1) reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; (3) reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide; and (6) contacting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide with methane sulfonic acid to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide mesylate.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20](=O)[CH2:21][CH2:22][C:23]([OH:25])=O)[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:28][NH2:29]>C(O)(=O)C>[C:1]1([S:7]([NH:10][CH:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:20]4[CH2:21][CH2:22][C:23](=[O:25])[NH:28][N:29]=4)[CH:17]=3)[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc3c(c2)CC(NS(=O)(=O)c2ccccc2)C3)=NN1

Procedure:
3.0 g (8 mmol) of 4-(2-benzenesulphonamido-indan-5-yl)-4-oxobutyric acid and 0.53 g (10.4 mmol) of 99% hydrazine hydrate in 12 ml of glacial acetic acid are boiled for 3 hours. The mixture is evaporated in vacuo, water is added to the residue, which is neutralised with sodium carbonate solution, and the reaction product is filtered off with suction and recrystallised from n-propanol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.OO.[ClH:11]>>[Cl:11][C:6]1[C:5]([OH:8])=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cl
Reactant: Cc1ccc(O)cn1
Agent: OO
Product: Cc1ccc(O)c(Cl)n1
Temperature: 80 °C

Procedure:
In 500 ml conc. hydrochloric acid was dissolved 50.0 g (0.46 mole) 6-methyl-3-hydroxypyridine. After heating to 80° C., 150 ml 15% hydrogen peroxide was slowly added over several hours while maintaining the reaction temperature at 80°-85°. The reaction mixture was cooled to 50° C. and concentrated under reduced pressure. The residue was brought to pH 8 by careful addition of 25% sodium hydroxide solution. This mixture was extracted with ether. The solvent was removed and the residue recrystallized one time from water and one time from benzene to provide pure 2-chloro-6-methyl-3-hydroxypyridine, mp 190°-191° C. CL EXAMPLE IV
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl/[C:6](=[N:11]\[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[CH:21]1[CH2:23][CH2:22]1)/[C:7]([F:10])([F:9])[F:8]>C(#N)C>[CH:21]1([C:13]2[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[N:11]2[C:6]([C:7]([F:10])([F:9])[F:8])=[N:3][N:2]=[N:1]2)[CH2:23][CH2:22]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=[N+]([O-])c1ccc(C2CC2)c(/N=C(\Cl)C(F)(F)F)c1
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C2CC2)c(-n2nnnc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of NaN3 (0.56 g, 8.57 mmol, 2.5 eq) and (Z)—N-(1-chloro-2,2,2-trifluoroethylidene)-2-cyclopropyl-5-nitrobenzenamine intermediate (1.0 g, 3.43 mmol, 1.0 eq) in 15 mL dry acetonitrile was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-cold aqueous Na2CO3 solution, extracted with ethyl acetate. The organic layer washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude mixture was purified by column chromatography, eluting with n-hexane:ethyl acetate (10-50% EtOAc in increments of 10% EtOAc)), giving the desired product in 37% overall yield (1.55 g).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:13][C:12]([CH:22]([CH3:24])[CH3:23])=[CH:11][C:10]=1[CH:25]([CH3:27])[CH3:26])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH:25]([C:10]1[CH:11]=[C:12]([CH:22]([CH3:24])[CH3:23])[CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:9]=1[OH:8])([CH3:26])[CH3:27]
Reactant: CC(C)c1cc(-c2ccc(F)cc2)c(OCc2ccccc2)c(C(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(-c2ccc(F)cc2)c(O)c(C(C)C)c1
Yield: 92.9 %

Procedure:
4 g of 10% Pd on carbon are added to a solution of 49.3 g (0.136 mol) of the benzyl ether from step 4 in 1 l of ethyl acetate and 100 ml of glacial acetic acid and the mixture is shaken in a hydrogen atmosphere (vigorous absorption of H2) for 20 minutes. The catalyst is filtered off, the filtrate is concentrated, the residue is taken up several times in toluene and the solution is in each case concentrated in vacuo. 34.4 g of the title compound are obtained as a colorless oil, b.p. 115° C./0.1 torr.
Reaction SMILES: [CH:1]1([NH:5][C:6]([C:8]2[N:9]([CH3:24])[C:10]([CH3:23])=[CH:11][C:12](=[O:22])[C:13]=2[O:14]CC2C=CC=CC=2)=[O:7])[CH2:4][CH2:3][CH2:2]1>[Pd].C(O)C>[CH:1]1([NH:5][C:6]([C:8]2[N:9]([CH3:24])[C:10]([CH3:23])=[CH:11][C:12](=[O:22])[C:13]=2[OH:14])=[O:7])[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)n1C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(=O)c(O)c(C(=O)NC2CCC2)n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51.5 %

Procedure:
A mixture of N-cyclobutyl-3-benzyloxy-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide (1.528 g, 4.68 mmol, 1.0 equiv), 10% Pd on activated carbon (200 mg, wet), and ethanol (200 ml) was stirred under 50 psi of H2 at room temperature for 2.5 h. The catalyst was filtered through Celite and the filtrate was evaporated to give a solid, which was recrystallized from MeOH gave the titled compound (0.57 g, 51.5%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH:5]C)=[CH2:3].[O:7]=[CH:8][C:9](=[CH2:11])[CH3:10].[CH:12]([Mg]Br)(C)C.[Cl-].[NH4+]>C(OCC)C>[CH3:11][C:9]1([CH:8]=[O:7])[CH2:5][CH2:4][C:2]([CH3:3])=[CH:1][CH:10]1[CH3:12]
Reactant: C=C(C)C=O
Reactant: CC(C)[Mg]Br
Reactant: C=C(C)C=CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1=CC(C)C(C)(C=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,2,4-trimethyl-3-cyclohexene-1-carboxaldehyde was prepared by a Diels-Alder reaction between 2-methyl1,3-pentadiene and methacrolein (prepared by Mannich-chemistry). To this aldehyde (15 g, 0.1M) in 100 ml diethyl ether, cooled in an ice bath, was added via a syringe isopropylmagnesium bromide (60 ml, 2.0M solution in diethyl ether). The reaction mixture was stirred for 2 hours and allowed to warm to ambient temperature then poured slowly into a dilute aqueous solution of ammonium chloride. The organic phase was separated and the aqueous phase extracted with more diethyl ether (50 ml). The organic extracts were combined, washed with water, dried with magnesium sulphate, filtered and solvent removed via rotary evaporation (rotavap). The crude was analysed by GC then GCMS. 4 product peaks of relative peak area (hereinafter to as “rpa”) 77.6%, 8.5%, 5.2% and 4.1% were shown to have MWs 154, 154, 196, 196, respectively. Hence the 2 major products were not the required isopropyl additions, but were comparable to the starting aldehyde being reduced to the corresponding alcohol, having the following structure:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]([N:22]([CH2:29][CH3:30])[CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:15]([CH3:21])=[C:16]([CH:20]=2)[C:17]([OH:19])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:64][CH2:65][C:66]1[C:67](=[O:74])[NH:68][C:69]([CH3:73])=[CH:70][C:71]=1[CH3:72]>CN(C=O)C.O>[CH3:72][C:71]1[CH:70]=[C:69]([CH3:73])[NH:68][C:67](=[O:74])[C:66]=1[CH2:65][NH:64][C:17]([C:16]1[CH:20]=[C:12]([CH:10]2[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH:13]=[C:14]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:15]=1[CH3:21])=[O:19]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCN(c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(C(=O)O)c1C)C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(c1cc(C2CN(C(=O)OC(C)(C)C)C2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
To a stirred solution of 5-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoic acid (54 mg, 0.13 mmol) in DMF (2 ml) and the reaction was cooled using an ice bath followed by the addition of DIPEA (45 μl, 0.26 mmol) and HATU (59 mg, 0.15 mmol)). The reaction was stirred at 0° C. for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 24 mg, 0.14 mmol) was added and the reaction was warmed room temperature for 16 h. The reaction mixture was then poured onto 50 ml of water and the aqueous phase was extracted with EtOAc (3×50 ml), washed with brine (50 ml) dried (Na2SO4), filtered and evaporated to give an oil. The product was then purified using a 5 g silica Isolute column eluting with 0% to 2.5% MeOH in DCM and evaporated to afford tert-butyl 3-(3-{[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]carbamoyl}-5-[ethyl(oxan-4-yl)amino]-4-methylphenyl)azetidine-1-carboxylate as a colourless oil (29 mg). LC-MS 90%, m/z=553.3. This material was dissolved in 4M HCl in dioxane solution (3 ml) and stirred at room temperature for 90 min after which the solvent was evaporated to dryness and the compound purified by preparative HPLC to afford the title compound as a white solid (11 mg, 8% over 2 steps). LC-MS 97%, 2.17 min (7 minute LC-MS method), m/z=453.2, 1H NMR (500 MHz, MeOD) δ 7.26 (s, 1H), 7.18 (s, 1H), 6.14 (s, 1H), 4.48 (s, 2H), 4.39 (s, 2H), 4.22 (s, 3H), 3.93 (d, J=10.5 Hz, 2H), 3.40-3.33 (m, 2H), 3.29-2.90 (m, 3H), 2.40 (s, 3H), 2.31 (s, 3H), 2.26 (s, 3H), 1.68 (d, J=26.3 Hz, 4H), 0.87 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH:26]([F:28])[F:27]>O.O1CCOCC1>[F:27][CH:26]([F:28])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: FC(F)Cl
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCOc1ccc(-c2ccc(OC(F)F)cc2)cc1
Temperature: 70 °C

Procedure:
A mixture of 20 g of 4-hydroxy-4'-octyloxybiphenyl, 13.6 g of NaOH, 100 ml of water and 150 ml of dioxane is heated to 70° C. with stirring. 10 g of chlorodifluoromethane are passed into the cooled two-phase mixture with vigorous stirring. The reaction mixture is poured into water, and the product is extracted with petroleum ether. The organic phase is dried over Na2SO4, evaporated, and the residue is filtered through a short silica gel column using petroleum ether as eluent. The product is recrystallized from acetonitrile. Colorless crystals are obtained. m.p.: 104° C., c.p.: 20° C. (extrapolated), Δn=0.093, viscosity: 17.