Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=[O:13].[OH-].[K+:18]>CO>[O:13]=[C:12]([CH:14]=[CH:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11]([O-:16])=[O:15].[K+:18]
Reactant: CC(=O)C(=O)O
Reactant: O=C/C=C/c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=CC=Cc1ccccc1
Temperature: 2.5 °C
Yield: 61 %

Procedure:
A solution of trans-cinnamaldehyde (26.43 g) and pyruvic acid (11.9 mL) in 10 mL of methanol was stirred and chilled to 0-5° C. in an ice bath. To the chilled solution was added 35 nL of potassium hydroxide (16.83 g in 50 mL of methanol) over a period of 20 minutes. The remaining methanolic potassium hydroxide was added rapidly and the ice bath was removed. The solution changed from a yellow to a dark orange and the precipitate was formed. The reaction mixture was chilled in the refrigerator overnight and the solid was collected by filtration, washed with 50 mL of methanol three times, 50 mL of ether and then air dried to afford 29.3 g of the desired 2-oxo-6-phenyl-3,5-hexadienoate as a yellow solid (61.0%). 1H NMR (DMSO-d6/D2O, 300 MHz), δ(ppm) 7.48 (d, 2H), 7.28 (m, 4H), 7.12 (d, 2H), 6.27 (d, 1H).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Fc1ccccn1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ccccn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-fluoro-pyridine following a procedure analogous to that described in Example 19. LC (method 9): tR=1.46 min; Mass spectrum (ESI+): m/z=389 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6](N)[CH:7]=[CH:8][C:9]=2[F:10])[CH2:3][CH2:2]1.[I-:12].[Cs+].II.N(OCCC(C)C)=O>COCCOC>[CH:1]1([C:4]2[CH:5]=[C:6]([I:12])[CH:7]=[CH:8][C:9]=2[F:10])[CH2:3][CH2:2]1
Reactant: Nc1ccc(F)c(C2CC2)c1
Reactant: [I-]
Agent: CC(C)CCON=O
Agent: II
Agent: [Cs+]
Solvent: COCCOC
Product: Fc1ccc(I)cc1C1CC1
Temperature: 60 °C
Yield: 71.9 %

Procedure:
To a solution of 3-cyclopropyl-4-fluorophenylamine (210 mg, 1.39 mmol) in DME (1.5 ml) was added caesium iodide (360 mg, 1.39 mmol), cuprous iodide (82 mg, 0.43 mmol), iodine (176 mg, 0.70 mmol) and isoamyl nitrite (1.11 ml, 8.34 mmol). The reaction mixture was heated to 60° C. for 2 h. The reaction mixture was cooled to RT and partitioned between pentane and sat. NH4Cl solution. The organic layer was separated, washed with 5% sodium thiosulfite and brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (100% pentane) to yield the desired 2-cyclopropyl-1-fluoro-4-iodobenzene (262 mg, 72%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): 7.40 (m, 1H), 7.17 (m, 1H), 6.76 (m, 1H), 2.02 (m, 1H), 1.03-0.96 (m, 2H), 0.74-0.68 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[N:12]=[C:11](Cl)[C:10]=1[C:24]#[N:25].[C:26]1([CH:32]([NH2:40])[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.NCC1C(N2CCOCC2)=NC2N(C)C(=O)N(C)C(=O)C=2C=1C1C=C(F)C=CC=1Br>>[NH2:25][CH2:24][C:10]1[C:11]([NH:40][CH:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:12][C:13]2[N:14]([CH3:22])[C:15](=[O:21])[N:16]([CH3:20])[C:17](=[O:19])[C:18]=2[C:9]=1[C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: NC(Cc1ccccc1)c1ccccc1
Reactant: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(C#N)c(Cl)nc2n(C)c1=O
Agent: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(CN)c(N3CCOCC3)nc2n(C)c1=O
Product: Cn1c(=O)c2c(-c3cc(F)ccc3Br)c(CN)c(NC(Cc3ccccc3)c3ccccc3)nc2n(C)c1=O

Procedure:
The title compound was prepared from Compound 47a (Example and 1,2-diphenylethanamine, according to procedure described in the synthesis of Compound 47. MS [m+H] calc'd C30H28BrFN5O2 588; found 588.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[CH2:9]2)=[CH:4][C:3]=1[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:48]([C:50]1[N:51]=[C:52]([C:63]([O-])=[O:64])[N:53]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:54]=1)#[N:49].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:17]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:63]([C:52]2[N:53]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:54]=[C:50]([C:48]#[N:49])[N:51]=2)=[O:64])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CN1C(=O)CC(c2ccc(N)c(C3=CCCCC3)c2)CC1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1C(=O)CC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1=O
Yield: 26.6 %

Procedure:
A solution of 266 mg (0.891 mmol) of 4-(4-amino-3-cyclohex-1-enyl-phenyl)-1-methyl-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 623 mg (1.34 mmol) of PyBroP, 300 mg (0.981 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 466 μL (2.67 mmol) of DIEA at RT for 16 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromagography of the residue on a 50-g Varian MegaBond Elut SPE column with 25% EtOAc-hexane afforded 130 mg (27%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C29H37N5O4Si, 548.3 (M+H). found 547.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.Cl>C(Cl)(Cl)(Cl)Cl.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[CH2:8][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
5-Fluoro-2-nitrotoluene (1.55 g, 10 mmol), N-bromosuccinimide (1.82 g, 10 mmol), and benzoyl peroxide (0.1 g, 0.4 mmol) were dissolved in CCl4 (50 mL), heated at reflux, and irradiated with light (100 W bulb) for 4 hours. The reaction mixture was filtered and concentrated. The residue was dissolved in THF (50 mL). Morpholine (1.9 g, 22 mmol) was added to the THF solution. The mixture was stirred at ambient temperature for 1 hour and then filtered. The solvent of the filtrate was evaporated. The bright orange residue obtained was then mixed with 5% HCl solution (30 mL) and extracted with ethyl acetate (2×25 mL). The aqueous layer was basified with NaOH solution to pH 8 and then extracted with methylene chloride. Both ethyl acetate solution and methylene chloride solution were dried over anhydrous Na2SO4 separately. Evaporation of ethyl acetate solution afforded an orange oil which was recrystallized from hexane:ether solution to yield 450 mg of a yellow solid, 4-(3-methyl-4-nitrophenyl)morpholine (18%), the by-product. Evaporation of methylene chloride solution afforded 660 mg of the desired compound, 4-(5-fluoro-2-nitrobenzyl)morpholine (27.5%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][N:8]=[N:9][C:10]=2NN)[CH:6]=1.Cl.C1C=CC2C(=CN=NC=2O)C=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[N:8][N:9]=1
Reactant: NNc1nncc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: Oc1nncc2ccccc12
Product: Clc1nncc2ccccc12

Procedure:
In another major embodiment of this invention, a process of preparing pure hydralazine hydrochloride is disclosed, comprising the steps of: a) reacting phthalazinone with phosphorous oxychloride at a specific temperature to produce 1-chlorophthalazine salt; b) concentrating the reaction mixture by distillation; c) isolating the 1-chlorophthalazine salt concentrated in step (b) by precipitating 1-chlorophthalazine salt through the addition of a mineral add in the presence of a solvent, filtering the resulting solid precipitated 1-chtorophthalazine salt, and drying; d) reacting the isolated and dried 1-chlorophthalazine salt with hydrazine hydrate without any substantial amount of organic solvent present and precipitating the resulting hydralazine base by adding a solvent; e) purifying the hydralazine base in a non-aqueous medium; f) converting the purified hydralazine base to hydralazine hydrochloride in a non-aqueous medium, and isolating the same; and g) purifying the isolated hydralazine hydrochloride by dissolving hydralazine hydrochloride in hot water to make a solution, treating the solution with a color adsorbent and a chelating agent, filtering off the adsorbent and chelating agent, adjusting the pH of the solution using a base or acid, and precipitating hydralazine hydrochloride by adding a water miscible solvent at a lower temperature.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:45])[C:9]([C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)([CH3:34])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[C:19]([C:27]([S:30]([CH3:33])(=[O:32])=[O:31])([CH3:29])[CH3:28])[CH:20]=[C:21]4[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]4)[CH:12]=2)=[CH:4][CH:3]=1.[CH3:46][Mg]I>C(Cl)Cl.[Cl-].[NH4+].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:45])([C:9]([C:35]2[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:39][CH:40]=2)([CH3:34])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:18]=[C:19]([C:27]([S:30]([CH3:33])(=[O:31])=[O:32])([CH3:28])[CH3:29])[CH:20]=[C:21]4[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]4)[CH:12]=2)[CH3:46])=[CH:4][CH:3]=1
Reactant: C[Mg]I
Reactant: CC(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)(C(=O)c1ccc(F)cc1)c1ccc(S(C)(=O)=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(O)(c1ccc(F)cc1)C(C)(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Temperature: 21 °C
Reaction time: 12 h

Procedure:
To a solution of Example 19 (93 mg, 0.144 mmol) in CH2Cl2 (4 mL) at −78° C. was added methyl magnesium iodide (3M, Et2O, 0.24 mL, 0.8 mmol) dropwise. The resulting reaction mixture was stirred at 21° C. for 12 h, then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with dichloromethane/methanol, 99:1, 2×), then stirring vigorously the resulting residue in hexane/ethyl acetate/ether for 1 h and then filtration afforded the title compound as a white powder (mixture of diastereoisomers; 1:1).
Reaction SMILES: [CH3:1][CH:2]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)C.Cl[CH2:20][CH2:21][N:22]=[C:23]=[S:24]>C(N(CC)CC)C>[CH3:1][CH:2]([N:8]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:23]1[S:24][CH2:20][CH2:21][N:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: S=C=NCCCl
Reactant: CCCCCC(C)NCc1cccnc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCC(C)N(Cc1cccnc1)C1=NCCS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To 3.1 g. of N-(1-methylhexyl)-[(3-pyridyl)methyl]amine dissolved in approximately 20 ml. of ethanol-free chloroform was added 1.8 g. of 2-chloroethylisothiocyanate followed by 2.08 ml. of triethylamine. The reaction mixture was stirred at room temperature overnight and then refluxed for approximately 4 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica gel while eluting with chloroform/acetone to afford approximately 4.0 g. of the desired product. Yield 91%.
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:15](OC)(=[O:20])[CH2:16][C:17]([CH3:19])=O>C(O)(=O)C>[C:1]([N:5]1[C:9]2[NH:10][C:15](=[O:20])[CH:16]=[C:17]([CH3:19])[C:8]=2[C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1nc(C2CCC2)cc1N
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(=O)[nH]c2c1c(C1CCC1)nn2C(C)(C)C
Temperature: 105 °C
Reaction time: 19 h
Yield: 10.4 %

Procedure:
To 2-tert-butyl-5-cyclobutyl-2H-pyrazol-3-ylamine (5.0 g, 25.9 mmol) in acetic acid (25 mL) was added methyl acetoacetate (5.5 mL, 51.8 mmol), and the reaction was heated to 105° C. After 19 hr, the reaction mixture was cooled to room temperature, concentrated to a viscous oil, and then taken up in EtOAc. The reaction mixture was quenched by the slow addition of an aqueous solution of NaHCO3. The layers were separated and the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of this material was accomplished by trituration with hexanes to give, after two crops, the title compound (0.7 g, 52% yield) as a colorless solid. 400 MHz 1H NMR (CD3OD) d 6.09 (s, 1H), 3.83 (dddd, J=8.3, 8.3, 8.3, 8.3 Hz, 1H), 2.50-2.27 (m, 7H), 2.08-2.01 (m, 1H), 1.99-1.85 (m, 1H), 1.71 (s, 9H). LRMS m/z (APCI+) 260 (M+1).
Reaction SMILES: [CH2:1]([N:13]=[C:14]=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:16].Cl.Cl.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:25][CH2:24]1.C(N(CC)CC)C>C(Cl)Cl>[ClH:36].[ClH:16].[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:26]2[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:14]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:15])[CH2:28][CH2:27]2)=[CH:31][CH:32]=1
Reactant: CCCCCCCCCCCCN=C=O
Reactant: NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNC(=O)NCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 116.3 %

Procedure:
The procedure described in Example 29 was followed using n-dodecyl isocyanate (2.11 g; 10 mmole), 1-(3-aminopropyl)-4-(4-chlorobenzyl)piperazine trihydrochloride (3.77 g; 10 mmole) methylene chloride (100 ml), and triethylamine (3.03 g; 30 mmole). Recrystallization from water provided the title compound (3.21 g; 58% yield) as colorless crystals, m.p. 215°-222° C.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][CH:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-phenylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=447.
Reaction SMILES: C(O[C:4](=[O:17])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([Br:15])[C:8]=1[OH:16])C.C([O-])([O-])=O.[K+].[K+].C(Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]2[C:8](=[C:9]([Br:15])[CH:10]=1)[O:16][C:4](=[O:17])[CH:5]=[CH:6]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)/C=C/c1cc(OC)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1ccc2cc(OCc3ccccc3)cc(Br)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
Dissolve preparation 2 (66.5 g, 275.89 mmol) in 1.5 L of dry DMF. Add finely powdered (325 mesh) K2CO3 (91.56 g, 662.13 mmol) followed by benzyl bromide (56.63 g, 331.07 mmol). Stir rapidly at room temperature overnight. Add 2 L of EtOAc, wash with H2O (1×2 L), 10% LiCl (3×, 4 L total volume) and brine. Dry over Na2SO4, filter and civ to yield a brown solid. Dissolve in hot EtOAc (2 L), filter off an insoluble brown solid, add hexane (˜500 mL) and allow to cool slowly, overnight. Filter off the resultant brown solid. This yields 50.3 g of a dark brown material. A second crop crashes out of the filtrate. This yields 8.1 g of a tan solid. Reduce the filtrate volume to ˜500 mL and placed on a plug of silica gel (1 kg, eluted with 1:1 EtOAc/hexane) to yield an additional 14.9 g of a darker brown solid. The total combined yield is 73.3 g (80%) of preparation 3. NMR (DMSO-d6) δ 7.96 (d, J=9.2 Hz, 1H), 7.58 (d, J=2.6 Hz, 1H), 7.45-7.32 (m, 6H), 6.53 (d, J=9.7 Hz, 1H), 5.15 (s, 2H).
Reaction SMILES: [CH2:1]([OH:12])[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O>CCCCCC>[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:12][CH2:1][C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1)=[O:22]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: COc1ccc(CO)cc1OC
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(COC(=O)CCCCCCC(C)C)cc1OC
Temperature: 50 °C
Yield: 89.1 %

Procedure:
Veratryl alcohol (734 mg, 4.53 mmol), 8-methylnonanoic acid (751 mg, 4.35 mmol) and Novozyme 435 (51 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (n-hexane:ethyl acetate=3:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give veratryl 8-methylnonanoate (1.25 g, yield 89.1%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[Cl:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([Si:41]([CH3:55])([CH3:54])[O:42][CH2:43][C@@H:44]1[CH2:53][N:52]2[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]2)[CH2:46][NH:45]1)([CH3:40])[CH3:39].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:33])([CH3:34])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[C@H:44]([CH2:43][O:42][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:54])[CH3:55])[CH2:53][N:52]4[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]4)[CH2:46]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[Cl:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:36])[F:35])[CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccc(F)cc1Cl
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccc(F)cc1Cl
Temperature: 100 °C
Yield: 25 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-chloro-4-fluorophenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D57, 60 mg, 0.11 mmol),), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 37 mg, 0.13 mmol), sodium t-Butoxide (13 mg, 00.1375 mmol) were degassed together in toluene (1.2 mL) for 10 minutes before adding bis(dibenzyleneacetone) palladium (6 mg, 0.011 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (11 mg, 0.0275 mmol) and heating at 100° C. for 30 minutes under microwave conditions. Added more bis(dibenzyleneacetone) palladium (6 mg, 0.011 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (11 mg, 0.0275 mmol) and heated for a further 30 minutes at 100° C. under microwave conditions. Diluted with EtOAc, washed with sat NaHCO3 solution ×1, brine ×1, dried (MgSO4). Filtered. Solvent evaporated under reduced pressure. Residue purified eluting with 0-100% EtOAc/Pent. Solvent evaporated to afford a brown gum of the title compound in 25% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][C:25]=2[CH3:26])[C:13]([NH:15][CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38]>O>[CH:18]1([CH2:17][CH2:16][NH:15][C:13](=[O:14])[C:12]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:10]([C:9]([NH:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][C:35](=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38])=[CH:3][CH:4]=3)=[O:27])[CH:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)Nc1ccc(N)nc1
Reactant: CC(C)CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)Nc1ccc(NC(=O)CC(C)C)nc1
Temperature: 0 °C

Procedure:
To a 25 mL round-bottomed flask was added N3-(6-aminopyridin-3-yl)-N1-(2-cyclopentylethyl)-4-methylisophthalamide (0.19 g, 0.52 mmol) and Triethylamine (0.18 ml, 1.3 mmol) to stir at 0° C. Isovaleryl chloride (0.14 ml, 1.0 mmol) was added to the solution dropwise. The reaction was allowed to stir for one hour. At which time was shown to be at completion by LC/MS. DI water was added to the reaction. The reaction was transferred to a separatory funnel, where the aqueous layer was extracted 3 times with DCM. The combined organic layers were washed with brine, saturated NaHCO3, dried with MgSO4, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (25M), eluting with a gradient of 1% to 10% MeOH in CH2Cl2, to provide N1-(2-cyclopentylethyl)-4-methyl-N3-(6-(3-methylbutanamido)pyridin-3-yl)isophthalamide as a white solid. MS (ESI, pos. ion) m/z: 451.3 (M+1).