Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[CH:9]=[CH:10]\[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25])/[C:3]([O:5]CC)=[O:4].[OH-].[K+].O>CO>[CH3:1]/[C:2](=[CH:8]\[CH:9]=[CH:10]\[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24][CH3:25])/[C:3]([OH:5])=[O:4]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\CC/C=C/C=C(\C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CC/C=C/C=C(\C)C(=O)O
Temperature: 65 °C

Procedure:
To a solution of ethyl (2E,4E,8Z,11Z,14Z,17Z)-2-methyl-icosa-2,4,8,11,14,17-hexaenoate (10) in methanol was added an aqueous solution of KOH (8 equiv.) and the mixture was heated to 60-70° C. for 2 hrs. The solution was cooled, water was added and the mixture acidified. The mixture was then extracted with ethyl acetate. The combined organic phases were washed with water and dried (MgSO4). Evaporation of the solvents under reduced pressure followed by flash chromatography on silica gel (8:2 hexane-EtOAc) gave the acid 11. δH(300 MHz): 0.96 (t, J 7.5, 3H, CH3), 1.91 (d, J 0.75, 3H, CH3), 2.08 (m, 2H), 2.2-2.4 (m, 4H), 2.7-2.9 (m, 6H), 5.2-5.5 (m, 8H), 6.11 (dt, J 15.0, J 6.5, 1H), 6.37 (dd, J 15.0, J 11.3, 1H), 7.26 (br d, J 11.3, 1H); δc(75 MHz) 12.16, 14.24, 20.53, 25.52, 25.61, 25.67, 26.57, 33.24, 124.44, 126.34, 126.97, 127.82, 128.04, 128.21, 128.54, 128.70, 128.74, 132.01, 140.79, 143.47, 174.28.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:18])[NH:10][C:11]([CH2:15][CH2:16][CH3:17])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([C:8]1[C:9](=[O:18])[N:10]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[C:11]([CH2:15][CH2:16][CH3:17])=[N:12][C:13]=1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C)c(Cc2ccccc2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(Cc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-benzyl-6-methyl-2-propylpyrimidin-4(3H)-one (0.80 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (1.08 g) in N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.17 g), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.61 g, 35%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([O:14][CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25]>C(Cl)Cl>[C:23]([O:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([O:14][CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: COC1(c2ccccc2)OCC(CO)O1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCC1COC(OC)(c2ccccc2)O1

Procedure:
The procedure of Example 1 was repeated, employing 21 grams (100 mmol.) of 4-hydroxymethyl-2-methoxy-2-phenyl-1,3-dioxolane, 25.3 grams (250 mmol.) of triethylamine, 9.5 grams (105 mmol.) of acryloyl chloride and 150 ml. of methylene chloride. The crude product was purified by column chromatography over basic alumina, using 15% (by volume) ethyl acetate in hexane as an eluant, to yield the desired 4-acryloyloxymethyl-2-methoxy-2-phenyl-1,3-dioxolane.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([CH2:9]O)[N:6]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:12])[CH2:5]1.[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]([C:11]([N:6]2[CH2:5][C:4](=[N:3][O:2][CH3:1])[CH2:8][C@H:7]2[CH2:9][N:29]2[C:25](=[O:35])[C:26]3[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:28]2=[O:30])=[O:12])=[CH:18][CH:17]=1
Reactant: CON=C1C[C@@H](CO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON=C1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reaction time: 48 h

Procedure:
A solution of alcohol (2) (EZ mixture, 51 mg, 0.16 mmol), phtalimide (70 mg, 0.48 mmol), triphenylphosphine polymer bound (158 mg, 0.48 mmol) and diethyl azodicarboxylate (40% in toluene, 205 μl, 0.48 mmol) in tetrahydrofuran (5 ml) was stirred for 2 days. The resin was filtered off and the reaction mixture was concentrated in vacuo. The crude was purified on silica gel preparative chromatography using DCM as eluant.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@@:11]2([F:20])[C:16]([O:18][CH3:19])=[O:17])(C(C)(C)C)(C)C.Cl>C(#N)C.CCOC(C)=O>[F:20][C@@:11]1([C:16]([O:18][CH3:19])=[O:17])[C@@H:12]2[C@H:10]1[C:9](=[O:8])[CH2:14][C@H:13]2[OH:15]
Reactant: COC(=O)[C@]1(F)[C@@H]2[C@H]1C(=O)C[C@H]2O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)[C@]1(F)[C@H]2[C@H](O)CC(=O)[C@H]21

Procedure:
TBS-ether 6′ (150 mg, 0.528 mmol) was treated with 1 M HCl (0.106 mL) in acetonitrile (0.8 mL) at rt for 2 h. The reaction was diluted with EtOAc, quenched by addition of a small amount of saturated aq. NaHCO3, washed with H2O and brine (twice), and dried over Na2SO4. The solvents were removed under reduced pressure, and the resulting residue was purified by flash silica gel column chromatography to afford hydroxy ketone 7′ as colorless solid: 1H NMR (CDCl3, 400 MHz) δ 4.60 (d, J=5.2 Hz, 1H), 3.72 (s, 3H), 2.67 (dd, J=5.2, 3.6 Hz, 1H), 2.42 (dd, J=5.2, 2.4 Hz, 1H), 2.34 (dd, J=18.9, 5.2 Hz, 1H), 2.22 (br-s, 1H), 2.08 (d, J=18.9 Hz, 1H), 1.93 (dd, J=3.6, 2.4 Hz, 1H); 13C NMR (CDCl3, 101 MHz) δ 208.8, 169.8, 68.3, 52.5, 42.7, 36.2, 34.2, 25.2.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22](=[S:24])[NH2:23])([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].Br[CH2:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33].N1C=CC=CC=1.O>C1COCC1>[CH2:35]([O:34][C:32]([C:31]1[N:23]=[C:22]([C:17]23[CH2:20][CH2:21][C:14]([C:7]4[NH:6][C:5]5[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=5[N:8]=4)([CH2:19][CH2:18]2)[CH2:15][CH2:16]3)[S:24][CH:30]=1)=[O:33])[CH3:36]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(N)=S)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CCOC(=O)C(=O)CBr
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCn1c(=O)c2[nH]c(C34CCC(c5nc(C(=O)OCC)cs5)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
A suspension of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbothioic acid amide (20 mg, 50 μmol) and KLCO3 (8.0 eq, 400 μmol) in THF (5 ml) was stirred vigorously for 5 min and ethyl bromopyruvate (29 mg, 150 μmol) was added neat via syringe. The resulting, pale yellow solution was stirred at rt for 1 h, cooled to 0° C. with the aid of an ice bath and treated sequentially with pyridine (8.0 eq, 400 μmol) and (F3CCO)2O (4.0 eq, 42 mg, 200 μmol). The resulting deep red solution was allowed to reach ambient temperature overnight. Following the addition of water (4 ml), the mixture was concentrated in vacuo and extracted with CH2Cl2 (2×10 ml). The combined organic phases were washed with 2 N HCl, dried (Na2SO4), filtered and concentrated in vacuo. The solution was purified by radial chromatography (1 mm plate) using 2-5% MeOH in CH2Cl2 as eluent to afford a white solid (22 mg, 88%). MS: 500 (MH+).
Reaction SMILES: [ClH:1].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[ClH:1].[NH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: c1ccc2ncccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: c1ccc2c(c1)CCCN2
Yield: 100 %

Procedure:
By operating under the same conditions, but substituting 132 mg of 2,6-lutidine hydrochloride, 165 mg of quinoline hydrochloride and, respectively, 169 mg of 1,2,3,4-tetrahydroquinoline hydrochloride for pyridine hydrochloride, there is obtained 600 mg (25%) 560 mg (24%) and, respectively, 780 mg (33%) of pure product.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([CH3:5])=O.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[CH:3]([NH:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:5]
Reactant: CC(=O)C(F)(F)F
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(NCc1ccccc1)C(F)(F)F
Yield: 98.4 %

Procedure:
After briskly stirring a mixture of 1,1,1-trifluoroacetone (1.0 ml; 11.2 mmol), benzylamine (1.1 ml; 10 mmol), AcOH (2 ml) and 3 Å molecular sieves (5 g) in 30 ml of CH2Cl2 for 2 hour at room temperature, sodium triacetoxyborohydride (4.25 g; 20 mmol) was added. After stirring 48 hours at room temperature, the reaction mixture was filtered through celite. After removing the volatiles in vacuo the residue was partitioned between ether (100 ml) and 1N NaOH (100 ml). The organic layer was washed with brine (50 ml), dried (MgSO4) and filtered through a 5×5 cm pad of silica gel. The pad was rinsed with ether and the filtrate was concentrated to afford 2.0 g (99%) of the title compound of this step as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([OH:12])[CH:5]=1.[F:14][C:15]([F:29])([F:28])[O:16][CH2:17][CH2:18][CH2:19]OS(C(F)(F)F)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[C:6]([O:12][CH2:19][CH2:18][CH2:17][O:16][C:15]([F:29])([F:28])[F:14])[CH:5]=1
Reactant: O=S(=O)(OCCCOC(F)(F)F)C(F)(F)F
Reactant: CCc1ccc(C(=O)OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1ccc(C(=O)OC)cc1OCCCOC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-ethyl-3-hydroxy-benzoic acid methyl ester (250 mg, 1.32 mmol), crude trifluoro-methanesulfonic acid 3-trifluoromethoxy-propyl ester (590 mg, 1.58 mmol; purity of 74%) and anhydrous K2CO3 (276 mg, 1.98 mmol) in MeCN (2.0 mL) is stirred in a sealed glass vial overnight at room temperature. The crude product obtained after filtration and evaporation is purified by flash chromatography (hexane/AcOEt 1:1) to give the title compound as oil. TLC, Rf (hexane/AcOEt 3:1)=0.38. 1H-NMR (CDCl3): δ 1.24 (t, 3H), 2.25 (m, 2H), 2.70 (q, 2H), 3.94 (s, 3H), 4.18 (t, 2H), 4.24 (t, 2H), 7.25 (d, 1H), 7.52 (s, 1H), 7.64 (d, 1H) ppm. 19F-NMR (CDCl3): δ −61.1 ppm.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:5]=2[O:6][C:7]=1[CH3:8].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].O>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]2[C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]=1[CH2:2][N:20]1[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]2[C:16]1=[O:26]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1oc2c([N+](=O)[O-])cccc2c1CCl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc2c([N+](=O)[O-])cccc2c1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
A mixture of 3-chloromethyl-2-methyl-7-nitrobenzo[b]furan (410 mg) and potassium phthalimide (506 mg) in N,N-dimethylformamide (10 ml) was stirred at ambient temperature for 3 hours. Then, the mixture was poured into cold water and the separated solid was collected, washed with water and dried to give 2-methyl-7-nitro-3-phthalimidomethylbenzo[b]furan (585 mg).
Reaction SMILES: FC1C=C(CN)C=NC=1.[O:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[N:12]=[CH:11]1.[CH3:17][C:18]1[N:19]=[C:20]([N:26]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:27]2=[O:38])[S:21][C:22]=1[C:23](O)=[O:24]>>[CH3:17][C:18]1[N:19]=[C:20]([N:26]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([F:35])([F:36])[F:37])[C:27]2=[O:38])[S:21][C:22]=1[C:23]([NH:16][CH2:15][C:13]1[N:12]=[CH:11][O:10][CH:14]=1)=[O:24]
Reactant: NCc1cocn1
Reactant: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CCCC(F)(F)F)C2=O)sc1C(=O)NCc1cocn1
Yield: 48 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with oxazol-4-ylmethanamine to react with 4-methyl-2-(2-oxo-3-(4,4,4-trifluorobutyl)imidazolidin-1-yl)thiazole-5-carboxylic acid in place of 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 48% yield: 1H NMR (300 MHz, CDCl3) δ 7.86 (s, 1H), 7.65 (s, 1H), 6.16-6.12 (m, 1H), 4.51 (d, J=5.4 Hz, 2H), 4.15-4.10 (m, 2H), 3.63-3.57 (m, 2H), 3.43-3.38 (m, 2H), 2.60 (s, 3H), 2.20-2.11 (m, 2H), 1.91-1.83 (m, 2H); 13C NMR (75 MHz, CDCl3) δ162.4, 157.3, 155.5, 152.8, 151.3, 151.2, 135.9, 135.8, 128.6, 124.9, 117.5, 42.9, 42.3, 41.9, 35.5, 31.7, 31.3, 30.9, 30.5, 20.2, 20.1, 17.2; MS (ES+) m/z 417.7 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C(O)(=[O:17])C>O.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[C:7](=[O:17])[CH2:8][CH2:9][C:10]2([CH3:14])[CH3:13]
Reactant: COc1ccc2c(c1)C(C)(C)CCC2
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A solution of 7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Intermediate 8, 1.65 g, 8.7 mmol) in 7.5 mL of glacial acetic acid was cooled to 0° C. and treated with a solution of chromium trioxide (2 g, 20 mmol) in 8 mL of acetic acid and 7 mL of water. The reaction mixture was then allowed to warm to ambient temperature and stirred overnight. It was diluted with water and extracted with diethyl ether (×2). The combined organic phase was washed with water (×1), saturated aqueous sodium bicarbonate (×1) and brine (×1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound (1.64 g, 93%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH3:15])[CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:17]([F:21])([F:20])(Br)Br>C1COCC1.CCOCC.[Zn]>[C:1]([O:5][C:6](=[O:16])[N:7]([CH:8]1[CH2:13][CH2:12][C:11](=[C:17]([F:21])[F:20])[CH2:10][CH2:9]1)[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(Br)Br
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(=O)CC1
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(=C(F)F)CC1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of methyl-(4-oxo-cyclohexyl)-carbamic acid tert-butyl ester (0.69 g, 3.04 mmol, 1.0 eq.) in THF (25 mL) at −30° C. was added CBr2F2 (1.25 mL, 4.5 eq.) followed slow addition of by P(N(CH3)2)3. The resulting mixture was warmed to room temperature over 0.5 h and Zn was introduced. The resulting mixture was stirred at reflux for 16 h, cooled to room temperature and diluted with Et2O. The organic phase was decanted and the aqueous phase extracted with 2×Et2O. The combined organic phase was washed with saturated CuSO4 solution until it stayed blue, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (20% EtOAc-Hexanes) to give (4-difluoromethylene-cyclohexyl)-methyl-carbamic acid tert-butyl ester (475 mg, 60%) as a white solid.
Reaction SMILES: [Br-].[CH2:2]([NH:5][CH2:6][CH2:7][CH2:8][N+:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3][CH3:4].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH-].[Na+]>CCO.O>[Br-:13].[CH2:14]([N:5]([CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][N+:9]([CH3:12])([CH3:11])[CH3:10])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCNCCC[N+](C)(C)C
Reactant: CCCCCCCCCCCCBr
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCN(CCC)CCC[N+](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a solution of propylamine (5.5 mL, 0.067 mol) in EtOH (100 mL) is added 3-bromo-N,N,N-trimethylpropan-1-aminium bromide (5.0 g, 0.0191 mol) portionwise at 0° C. over 20 minutes. The solution is warmed to room temperature and then refluxed for 4 hours. The solution is cooled to room temperature, and the solvent is removed via rotary evaporator to provide the crude di-bromo salt (5.69 g, 0.0179 mol). The salt is dissolved in MeOH (200 mL) and NaOH is added portionwise (0.717 g, 0.0179 mol) in MeOH (50 mL) over 30 minutes at room temperature. The solution is stirred an additional 2 hours at room temperature after addition is complete and then the solvent is removed via rotary evaporator. The residue is stirred with CH3CN (150 mL) for 30 minutes and the solids filtered off. The filtrate is concentrated via rotary evaporation and the residue is pumped on 24 h under vacuum to provide the 3-(propylamino)-N,N,N-trimethylpropan-1-aminium bromide (4.07 g, 0.017 mol), which is used without further purification. The 3-(propylamino)-N,N,N-trimethylpropan-1-aminium bromide (4.07 g, 0.017 mol) is dissolved in EtOH (100 mL) and 1-bromododecane (4.55 mL, 0.019 mol) is added dropwise over 15 minutes. The reaction is refluxed 24 hours, cooled to room temperature, and solid NaOH (0.68 g, 0.017 mol) is added. The reaction is stirred 2 hours at room temperature, and then the solids are filtered off. The filtrate is concentrated to give a white solid. The solid is dissolved in water (200 mL) and extracted with EtOAc (3×150 mL). The organic layers are combined and discarded, and the aqueous layer is frozen and lyophilized under vacuum for 48 hours to provide 3-(dodecyl(propyl)amino)-N,N,N-trimethylpropan-1-aminium bromide as a white solid (5.29 g, 0.013 mol).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9]([C:12]#[C:13][C:14]([CH3:17])([OH:16])[CH3:15])[C:8]2[CH:7]=[C:6](/[CH:18]=[CH:19]/[C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2>N1C=CC=CC=1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][C:2]1([CH3:30])[CH2:11][CH:10]=[C:9](/[CH:12]=[CH:13]\[C:14]([CH3:15])([OH:16])[CH3:17])[C:8]2[CH:7]=[C:6](/[CH:18]=[CH:19]/[C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(/C=C/c2ccc3c(c2)C(C#CC(C)(C)O)=CCC3(C)C)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(/C=C/c2ccc3c(c2)C(/C=C\C(C)(C)O)=CCC3(C)C)cc1
Yield: 58.8 %

Procedure:
A mixture of methyl 4-[(E)-(5,6-dihydro-5,5-dimethyl-8-(3-methyl-3-hydroxy-1-butyn-1-yl)-2-naphthalenyl)ethenyl]benzoate (0.228 g, 0.57 mmol) and 10% Pd/BaSO4 (75 mg) in pyridine (5 mL) was hydrogenated (rubber balloon) for 60 minutes at room temperature. The reaction mixture was then filtered through celite and the pad washed with ethyl ether. The filtrate was washed with water, 1N hydrochloric acid and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified on silica gel chromatography (dichloromethane/acetonitrile) to give the title material (135 mg, 59%) as a white solid.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=O.[CH2:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:21]>C(Cl)Cl>[CH2:20]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17](=[O:19])[CH2:16][CH2:15][O:14][CH3:13])[CH3:21]
Reactant: COCCC(=O)O
Reactant: CCNCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCN(Cc1ccccc1)C(=O)CCOC
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A suspension of 1,1′-carbonyldiimidazole (23.20 g, 0.14 mol) in dry DCM (240 mL) was added portion-wise over 15 min to a solution of 3-methoxypropionic acid (10.00 mL, 0.11 mol) in DCM (100 mL) under nitrogen at room temperature. The resulting solution was stirred under nitrogen for 1 h and then treated with a solution of N-ethylbenzylamine (32.70 mL, 0.22 mol) in dry DCM (140 mL) drop-wise over 50 min. The resultant pale brown solution was stirred under nitrogen at room temperature for 16 h and then reduced in vacuo. The orange residue was partitioned between EtOAc (500 mL) and saturated aqueous NaHCO3 (500 mL), the layers separated and the organic layer washed with aqueous HCl (2M, 500 mL) and brine (350 mL). Each of the aqueous washings was then re-extracted with EtOAC (250 mL) and the combined organic layer dried (MgSO4), filtered and reduced in vacuo to give a yellow oil. Purification by Biotage (silica, 5×90 g cartridges), eluting with cyclohexane:EtOAc 95:5 then 3:2 afforded the title compound as a pale yellow oil (20.39 g).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][CH2:5][N:6]1[C:11](=[O:12])[C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:9]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:8]=[C:7]1SC.[C:30]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[C:11](=[O:12])[N:6]3[CH:5]=[C:4]([CH3:3])[N:39]([CH2:38][CH2:37][CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:7]3=[N:8][C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:14][CH:15]=1
Reactant: NCCCc1ccccc1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1CC#C[Si](C)(C)C
Product: Cc1cn2c(=O)c(-c3ccc(F)cc3)c(-c3ccncc3)nc2n1CCCc1ccccc1
Temperature: 190 °C

Procedure:
A neat mixture of 3-(3-trimethylsilyl-2-propynyl)-5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone (50 mg, 0.12 mmol) and 3-phenyl-1-propylamine (67 mg, 0.47 mmol) was warmed to 190° C. for 17 h. After cooling to 23° C., the reaction mixture was applied directly to purification via flash chromatography (step gradient 1%MeOH:CHCl3 then 2%, then 3%;) to afford the desired product: MS (m/z) 439 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:23][N:24](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[C:23]([C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)#[N:24]
Reactant: CN(C)C=O
Reactant: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1nc(-c2cc(C#N)cc(C(F)(F)F)c2)co1
Temperature: 100 °C
Yield: 75 %

Procedure:
A suspension of methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)-propanoate (Reference Example 44, 0.645 g, 1.71 mmol) and zinc cyanide (0.120 g, 1.02 mmol) in DMF (15.0 mL) was evacuated and purged with nitrogen. To this reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.197 g, 0.170 mmol) and the resulting reaction mixture was heated at 100° C. for 8 h. After this time, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, hexanes/ethyl acetate 4:1) to provide methyl 3-(4-(3-cyano-5-(trifluoromethyl)phenyl)-oxazol-2-yl)propanoate (0.417 g, 75%) as a white solid.