Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C(=O)([O-])[O-].[K+].[K+].[NH2:39][C:40]1[CH:44]=[CH:43][NH:42][N:41]=1>CN1CCCC1=O.[Cu]>[NH2:39][C:40]1[CH:44]=[CH:43][N:42]([C:2]2[N:3]=[CH:4][C:5]([F:32])=[C:6]3[C:10]([C:11](=[O:31])[C:12]([N:14]4[CH2:15][CH2:16][N:17]([C:20]5[N:24]([C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:23]=[N:22][N:21]=5)[CH2:18][CH2:19]4)=[O:13])=[CH:9][NH:8][C:7]=23)[N:41]=1
Reactant: Nc1cc[nH]n1
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nc1ccn(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n1
Temperature: 160 °C
Yield: 15.9 %

Procedure:
A mixture of 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (100 mg, 0.2 mmol), potassium carbonate (26 mg, 0.2 mmol), copper (13 mg, 0.2 mmol) and 3-aminopyrazole (100 uL, 1 mmol) in N-methylpyrrolidinone (0.5 mL) was heated at 160° C. for 5 h. Solvent was removed in vacuum and residue was dissolved in DMF and purified using reverse phase prep HPLC to afford 1-(7-(3-amino-1H-pyrazol-1-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (15.9 mg) as a pale yellow solid; 1HNMR (500 MHz, DMSO) δ 8.34 (d, J=2.0 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.03 (s, 1H), 7.70-7.58 (m, 5H), 5.92 (d, J=2.5 Hz, 1H), 5.25 (m, 2H), 3.71 (m, 2H), 3.47 (m, 2H), 3.32 (m, 2H), 3.16 (m, 2H). LCMS: m/e 502 (M+H)+, ret time 1.26 min (method 3); and 1-(7-(5-amino-1H-pyrazol-1-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (8.8 mg) as a pale yellow solid; 1HNMR (500 MHz, CDCl3) δ 8.21 (m, 1H), 8.11 (bs, 1H), 7.60 (m, 6H), 6.94 (m, 2H), 5.52 (m, 1H), 3.71 (m, 2H), 3.47 (m, 2H), 3.31 (m, 2H), 3.16 (m, 2H); LCMS: m/e 502 (M+H)+, ret time 1.26 min (method 3).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].Br[CH:20]([CH2:26]Br)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CC(C)=O>[F:17][C:14]([F:15])([F:16])[C:12]1[CH:11]=[CH:10][C:9]2[O:18][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:26][NH:7][C:8]=2[CH:13]=1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2cc(C(F)(F)F)ccc2O1

Procedure:
11.4 g of potassium carbonate was added to 48.7 g of 7B in 320 ml of acetone. Then 18.2 of ethyl 2,3-dibromopropionate was added dropwise to the refluxing mixture. This procedure was repeated thrice. The mixture was refluxed for 17 hours and filtered, and the filtrate was stripped of solvent under reduced pressure. The residue was dissolved in ether; the solution was washed with dilute sodium hydroxide solution, then dried (MgSO4) and stripped of solvent. The residue was washed with petroleum ether and dried. The residue was mixed with ether and filtered. Part of the solvent was evaporated from the filtrate; the remaining solution was cooled. Crystals which formed were filtered and recrystallized from ether to give 7, m.p.: 105°-107°.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:10]([N:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CCCN
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCN(Cc1ccccc1)Cc1ccccc1
Yield: 91.2 %

Procedure:
Heat a solution of methyl 4-aminobutanoate hydrochloride (11 g, 71.9 mmol), benzylbromide (25.2 g, 147.3 mmol) and K2CO3 (21.8 g, 158.2 mmol) in MeCN (200 mL) at 40° C. overnight. Concentrate the mixture to dryness, pour the residue into water, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography to give the title compound (19.5 g, 91%). 1H NMR (400 MHz, DMSO-d6): δ 7.33-7.18 (m, 10H), 3.57 (s, 3H), 3.52 (s, 4H), 2.43-2.28 (m, 4H), 1.83-1.76 (m, 2H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:5]([N:10]2[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1>O.C(O)C>[Cl:3][C:4]1[C:5]([N:10]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]([C:20]([F:23])([F:21])[F:22])=[N:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Potassium hydroxide (0.5 g, 85%, 2.28 mmol) in water (1 mL) was added to ethyl 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (i.e. the product of Example 4) (0.66 g, 2.07 mmol) in ethanol (3 mL). After about 30 minutes, the-solvent was removed under reduced pressure, and the mixture was dissolved in water (40 mL). The solution was washed with ethyl acetate (20 mL). The aqueous layer was acidified with. concentrated hydrochloric acid and was extracted with ethyl acetate (3×20 mL). The combined extracts were dried and evaporated to give the product as a solid (0.53 g, 93% yield), m.p. 178-179° C. (after crystallization from hexanes-ethyl acetate).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH2:24]([N:31]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCCC1>[CH2:24]([N:31]1[CH2:37][CH2:36][CH2:35][N:34]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[N:3]=2)[CH2:33][CH2:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CN2CCCNCC2)cc1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCN(Cc3ccccc3)CC2)nc1-c1ccc(C)cc1
Yield: 59.8 %

Procedure:
This compound was prepared according to the method C from methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.095 g; 0.285 mmol), 1-benzyl-1,4-diazepane (0.178 g, 0.937 mmol) and triethyl amine (0.200 mL; 1.43 mmol) in tetrahydrofuran (2 mL). Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.083 g (54%) of the titled compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[F:12].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:15]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[F:12])[CH:14]=[CH2:13]
Reactant: O=C1OCc2c1ccc(Br)c2F
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1F)COC2=O

Procedure:
To a flask charged with 5-bromo-4-fluoro-2-benzofuran-1(3H)-one (52 mg, 0.22 mmol) and a stir bar was added allyl tri-n-butyltin (0.10 mL, 0.34 mmol), palladium tetrakis (39 mg, 0.034 mmol), lithium chloride (29 mg, 0.68 mmol), and toluene (5 mL). The mixture was purged three times with nitrogen, and heated to reflux for 4 hours. LC showed formation of the desired product, which was purified by silica gel chromatography to deliver 5-allyl-4-fluoro-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 193 [M+1]+;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN([CH:20]=[O:21])C>>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[C:7]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: COc1cc(F)cc(OC)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(F)c(C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of 1-fluoro-3,5-dimethoxybenzene (3.12 g, 20.0 mmol) in DMF (15 mL) was added dropwise phosphoryl trichloride (1.55 mL) at 0° C. The reaction mixture was stirred at room temperature overnight and poured onto ice. The resulting mixture was extracted with ethyl acetate (2×50 mL) and the combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc/PE=1/8) to give the title compound as a yellow solid (2.75 g, Yield: 74.6%). 1H NMR (400 MHz, DMSO-d) δ 10.15 (s, 1H), 6.52-6.56 (m, 2H), 3.91 (s, 3H), 3.88 (s, 3H). MS (ESI) m/z=185 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[C-:11]#[N:12].[K+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([OH:5])[C:11]#[N:12]
Reactant: [C-]#N
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC(O)c1c(Cl)cccc1Cl
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a stirred and cooled suspension of 438 g of 2,6-dichlorobenzaldehyde in 2000 g of glacial acetic acid there was added dropwise a solution of 203 g of potassium cyanide in 350 g of water, keeping the temperature below 25° C. Stirring was continued overnight at room temperature. The reaction mixture was concentrated and the residue, which solidified upon cooling, was filtered off and dried, yielding 438 g of (±)-2,6-dichloro-α-hydroxybenzeneacetonitrile; mp. 90° C. (interm. 1).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@H:4]([CH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:31]C)[CH:27]=3)[CH:22]=2)=[C:15]([Cl:33])[CH:14]=1)[NH:5]C(=O)C(F)(F)F.Br.C(O)(=O)C.[OH-].[Na+]>O>[Cl:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([Cl:33])[C:16]=1[O:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:31])[CH:27]=2)[CH:22]=1)[CH2:12][C@@H:4]([C:3]([OH:34])=[O:2])[NH2:5]
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(Oc2ccc3cc(OC)ccc3c2)c(Cl)c1)NC(=O)C(F)(F)F
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N[C@@H](Cc1cc(Cl)c(Oc2ccc3cc(O)ccc3c2)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
A mixture of 3,5-dichloro-N-trifluoroacetyl-O-[(6-methoxy)-2-naphthyl]-L-tyrosine methyl ester (160 mg, 0.31 mmol), 47% hydrobromic acid (3 ml) and acetic acid (2 ml) was heated under reflux for 5 hrs. The reaction mixture was diluted with water (10 ml), adjusted to pH 4-5 with 4N sodium hydroxide under ice cooling and then stirred at room temperature for 30 min. The precipitates were collected by filtration, washed with water and dried under reduced pressure to give 3,5-dichloro-O-[(6-hydoxy)-2-naphthyl]-L-tyrosine (92 mg, 76%) as a pale orange powder.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](Cl)=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:14][NH:15][O:16][CH3:17]>C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>[CH3:17][O:16][N:15]([CH3:14])[C:8](=[O:9])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: CNOC
Reactant: O=C(Cl)COc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CON(C)C(=O)COc1ccc(F)cc1
Reaction time: 0.33 h
Yield: 73 %

Procedure:
2-(4-Fluorophenoxy)ethanoic acid chloride was added slowly to a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (55.80 g, 572 mmol) in saturated K2CO3 and ethyl acetate (375 mL). A moderately exothermic reaction occurred (larger scale reactions are cooled with an ice bath), and after 20 minutes, the reaction mixture was partitioned between water and ether. The ether layer was washed with 1 M HCl and saturated NaCl, and dried over MgSO4. The dried solution was filtered and concentrated under vacuum to give N-methoxy-N-methyl-2-(4-fluorophenoxy)ethanamide, a compound of formula (Z), as a yellow oil which solidified to an off-white crystalline solid, 113.05 g (73% yield from starting acid); 1H NMR (CDCl3,400 mHz) δ 3.21 (s, 3H), 3.73 (s, 3H), 4.75 (s, 2H), 6.87 (m, 2H), 6.95 (m, 2H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:31]>O1CCOCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH2:31])=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(N)=O)c3)C(C)(C)C2=O)cc1
Temperature: 130 °C

Procedure:
To a solution of 250 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9 in 5 mL of dioxane are added 6.5 mL of a 7N solution of ammonia in methanol. The reaction mixture is heated by microwave at 130° C. for 3 hours and concentrated under reduced pressure. The residue is purified by HPLC (gradient: water/acetonitrile containing 0.1% formic acid) to give 54 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]methyl}pyridin-2-yl)urea, the characteristics of which are as follows:
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH3:24])[N:18]=[C:17]([C:25]([OH:27])=[O:26])[CH:16]=2)[CH2:11][CH2:10]1)=[O:7])(C)(C)C.Cl.O1CCOCC1.Cl.NC1CCN(C2C=C(C=C(Cl)N=2)C(N)=O)CC1.Cl.NC1CCN(C2N=C(CCCC)N=C(C(O)=O)C=2)CC1.[Cl:74][C:75]1[C:79]([Cl:80])=[C:78](C)[NH:77][C:76]=1[C:82](NC1CCN(C2C=C(C#N)N=C(Cl)N=2)CC1)=O>>[CH2:21]([C:19]1[N:18]=[C:17]([C:25]([OH:27])=[O:26])[CH:16]=[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([NH:8][C:6]([C:78]3[NH:77][C:76]([CH3:82])=[C:75]([Cl:74])[C:79]=3[Cl:80])=[O:7])[CH2:14][CH2:13]2)[N:20]=1)[CH2:22][CH2:23][CH3:24]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C#N)nc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: CCCCc1nc(C(=O)O)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: CCCCc1nc(C(=O)O)cc(N2CCC(N)CC2)n1
Agent: Cl
Agent: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Solvent: C1COCCO1
Product: CCCCc1nc(C(=O)O)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
(6-{4-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-2-butylpyrimidine-4-carboxylic acid) (Intermediate 100) was treated with 4 N HCl/dioxane for as described for Intermediate 70. The resulting hydrochloride salt, 6-(4-aminopiperidin-1-yl)-2-butylpyrimidine-4-carboxylic acid hydrochloride salt was coupled to 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3) in a manner analogous to Example 29 to give the title compound.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].P(OC)(OC)(OC)=O>O>[CH:2](=[O:1])[C:3]1[CH:11]=[CH:10][C:8]([O:9][CH3:12])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)ccc1O
Agent: [K+]
Solvent: O
Solvent: COP(=O)(OC)OC
Product: COc1ccc(C=O)cc1OC
Temperature: 85 °C
Yield: 98.5 %

Procedure:
In a three-neck flask (capacity 100 ml) equipped with a mechanical stirrer and reflux condenser, 5.00 g (0.033 mol) of vanillin and 5.00 g (0.036 mol) of anhydrous potassium carbonate were placed and the mixture was heated under a nitrogen atmosphere to 85° C. The mixture was a clear to amber melt of vanillin with carbonate in suspension. To this mixture was added 5.00 ml (0.043 mol) of trimethyl phosphate over about 5 minutes while maintaining the reaction temperature below 125° C. The mixture was maintained at about 80° C. for one hour and then cooled to 40° C. The mixture was poured into 20 ml water and extracted two times with 20 ml of methylene chloride. The combined extracts were dried over anhydrous potassium carbonate, filtered, and concentrated to give 5.4 g (99%) of veratraldehyde as a pale oil.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22].S(=O)(=O)(O)O>ClCCl.CN(C)C1C=CN=CC=1>[C:21]([O:1][C@H:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4])(=[O:23])[CH3:22]
Reactant: O=C(O)[C@H](O)CCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](CCc1ccccc1)C(=O)O
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A(ii)(a) A solution of 18 g of 2(R)-hydroxy-4-phenylbutanoic acid in 200 ml of dichloromethane containing 20.5 g of triethylamine and 250 mg of 4-(dimethylamino)pyridine was stirred at room temperature and treated dropwise with 12 g of acetic anhydride. The resulting mixture was stirred for a further 3 hours and then acidified by the addition of 125 ml of 2N sulphuric acid. The organic phase was separated and washed with two 100 ml portions of 2N sulphuric acid, then with 100 ml of water and finally with 100 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated in vacuo to give 22 g of 2(R)-acetoxy-4-phenylbutanoic acid as a colouless viscous oil; [α]43620 =+13.7° (c=1 in ethanol).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]([C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.C(OCC)(=O)C>[CH2:17]([N:15]1[CH:16]=[C:12]([C:10]([C:9]2[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[N:13]=[CH:14]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1c[nH]cn1)c1cccnc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1cn(Cc2ccccc2)cn1)c1cccnc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
Sodium hydride (60% in mineral oil, 23 mg, 0.58 mmol) was added to a solution of (2-fluoropyridin-3-yl)(1H-imidazol-4-yl)methanone (100 mg, 0.52 mmol) in tetrahydrofuran (3 ml), cooled to 0° C. The reaction mixture was then stirred for 30 minutes. Benzyl bromide (0.062 ml, 0.52 mmol) was added and the mixture was warmed up to room temperature. The reaction mixture was stirred for 18 hours, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound (100 mg, 68% yield).
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOCCOC.C(OCC)(=O)C>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:17]([Cl:22])[CH:16]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CCOC(=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOCCOC
Product: CCOC(=O)c1ccc(F)cc1Oc1ccc(N)cc1Cl
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2,4-difluorobenzoate (6.48 g) and 4-amino-2-chlorophenol (5.0 g) in diglyme (40 mL) was added K3PO4 (7.39 g). The mixture was stirred at 110° C. overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with water, brine and dried over Na2SO4. The mixture was filtered, and the solvent was evaporated and the residue was loaded on a column and eluted with 10% ethyl acetate in hexane to give the product.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[N:37]=[C:38]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][C:40]=1[CH2:41]O.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:41][C:40]3[S:39][C:38]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[N:37][C:36]=3[CH3:35])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Reactant: Cc1nc(-c2ccccc2)sc1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccccc2)sc1COc1ccc(-c2c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c2N2CCC(C)(C)CC2)cc1
Reaction time: 18 h
Yield: 34 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.053 mmol), (4-methyl-2-phenylthiazol-5-yl)methanol (32.9 mg, 0.160 mmol) and Ph3-resin (69.7 mg, 0.267 mmol) in THF (2 mL) was added DEAD (0.025 mL, 0.160 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (1.067 mL, 1.067 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-((4-methyl-2-phenylthiazol-5-yl)methoxy)phenyl)pyridin-3-yl)acetic acid (11.6 mg, 0.018 mmol, 34.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.89 (d, J=7.3 Hz, 2H), 7.52-7.41 (m, 4H), 7.25 (d, J=8.1 Hz, 1H), 7.14 (t, J=7.9 Hz, 2H), 7.10-7.04 (m, 1H), 5.82 (br. s., 1H), 5.41 (q, J=12.8 Hz, 2H), 3.26 (d, J=11.7 Hz, 1H), 2.77 (br. s., 1H), 2.47 (s, 3H), 2.43 (s, 3H), 2.15 (d, J=10.3 Hz, 1H), 2.07 (s, 3H), 1.88 (br. s., 1H), 1.46 (br. s., 1H), 1.24 (br. s., 1H), 1.15 (br. s., 1H), 1.12 (s, 9H), 0.92 (d, J=10.3 Hz, 1H), 0.77 (br. s., 3H), 0.51 (br. s., 3H). LCMS (M+H)=628.6.