Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:4]=[CH:5][NH:6][C:7](=O)[CH:8]=1.C1(P(Cl)([Cl:20])=O)C=CC=CC=1>>[Cl:20][C:7]1[CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[N:4]=[CH:5][N:6]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: O=c1cc(C(F)(F)F)nc[nH]1
Product: FC(F)(F)c1cc(Cl)ncn1
Temperature: 25 °C

Procedure:
Phenylphosphonic dichloride (107 ml) and 4-trifluoromethylpyrimidin-6-one (103 g) were heated at 130° C. under nitrogen for 30 minutes. The reaction was cooled to room temperature and the reaction flask was equipped with a short path distillation head. The bath temperature was raised to about 200° C. and the product distilled out of the reaction mixture. Fractional distillation of this material gave 80.8 g of 4-chloro-6-trifluoromethylpyrimidine as a colorless liquid (b.p.=134°-136° C. @ 760 mm Hg).
Reaction SMILES: C[C@H](N)C1C=CC=CC=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:15]([C@H:17]1[CH2:25][CH:24]=[CH:23][CH2:22][C@H:18]1[C:19]([OH:21])=O)=O.[ClH:31].Cl.[NH:33]1[CH2:38][CH2:37][CH:36]([NH:39][NH2:40])[CH2:35][CH2:34]1.C(N(CC)CC)C>C(O)CC>[ClH:31].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:15]2[C@@H:17]3[C@@H:18]([CH2:22][CH:23]=[CH:24][CH2:25]3)[C:19](=[O:21])[N:39]([CH:36]3[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]3)[N:40]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1OC
Reactant: NNC1CCNCC1
Agent: C[C@H](N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCO
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Temperature: 25 °C

Procedure:
A solution of 50 mmol of the salt of (S)-(−)-α-methylbenzylamine and (cis)-2-(3,4-dimethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid (starting compound A8), 55 mmol of piperidin-4-yl-hydrazine dihydrochloride and 100 mmol of triethylamine in 150 ml of 1-propanol is refluxed for 18 h. After cooling to RT, the precipitate is filtered off and dried. M.p. 285-288° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[N:7]=1.[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[S:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[N:7]=1
Reactant: O=Cc1nccs1
Reactant: N#Cc1cccc(-c2noc([C@@H]3CCCN3)n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: N#Cc1cccc(-c2noc([C@@H]3CCCN3Cc3nccs3)n2)c1

Procedure:
3-[5-(1-Thiazol-2-ylmethyl-pyrrolidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile (63.5 mg, 91%) was obtained as described in Example 43 from (S)-3-(5-pyrrolidin-2-yl-[1,2,4]oxadiazol-3-yl)-benzonitrile (49.8 mg, 0.18 mmol) reacted with thiazole-2-carbaldehyde (35.2 mg, 0.31 mmol) and sodium triacetoxyborohydride (72 mg, 0.34 mmol) is in dichloroethane (3 mL) at room temperature. 1H NMR (CDCl3), δ(ppm): 8.39 (s, 1H), 8.32 (d, 1H), 7.78 (d, 1H), 7.68 (d, 1H), 7.60 (t, 1H), 7.27 (d, 1H), 4.32 (dd, 1H), 4.27 (dab, 1H), 4.17 (dab, 1H), 3.31 (m, 1H), 2.81 (q, 1H), 2.39 (m, 1H), 2.25 (m, 1H), 2.14 (m, 1H), 2.04 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].CC(C)([O-])C.[K+].CCCCCC.C(OCC)(=O)C.Cl>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCCc1cccc(OCC)c1C(=O)O
Temperature: 68 °C
Yield: 16.6 %

Procedure:
To a stirred solution of Ethyl 2-Ethoxy-6-pentadecylbenzoate (20 g, 240 mmol) in dimethyl sulfoxide (80 mL) was added potassium tert-butoxide (20 g, 890 mmol) in portions. The solution was heated to 68° C. on a water bath for 3 h, the reaction was monitored by TLC using a hexane-ethyl acetate (9:1) solvent system. The reaction mass was cooled to 15° C., poured into ice water, and then acidified with 10% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in petroleum ether (50 mL) to yield an off-white solid of 2-Ethoxy-6-pentadecylbenzoic Acid (15 g, 80%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][NH:18]C(=O)OC(C)(C)C)[CH2:13][CH2:12]2)[N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:39](=[O:41])[CH3:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C[Si](Cl)(C)C>CCCCO>[NH2:18][CH2:17][CH:14]1[CH2:13][CH2:12][N:11]([C:4]2[N:3]=[C:2]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH2:34][CH2:35][N:36]([C:39](=[O:41])[CH3:40])[CH2:37][CH2:38]4)=[CH:31][CH:32]=3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)nc3[nH]cnc23)CC1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(N4CCC(CN)CC4)c4nc[nH]c4n3)cc2)CC1
Yield: 9.8 %

Procedure:
A mixture of tert-butyl (1-(2-chloro-9H-purin-6-yl)piperidin-4-yl)methylcarbamate (100 mg, 0.272 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (120 mg, 0.548 mmol) and trimethylsilyl chloride (0.300 mL, 2.37 mmol) in n-BuOH (4 mL) was stirred at 135° C. for 70 h. n-BuOH was removed in vacuo. The residue was purified by HPLC to give the titled compound (12 mg). MS 450.6 (M+H); UV 200.0, 270.8 nm.
Reaction SMILES: [OH:1][CH2:2][CH:3]([S:16][CH2:17][P:18]([O:23]CC)([O:20]CC)=[O:19])[CH2:4][O:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][CH:9]=[N:10][C:11]=2[NH2:15].Br[Si](C)(C)C>ClCCl>[OH:1][CH2:2][CH:3]([S:16][CH2:17][P:18]([OH:20])([OH:23])=[O:19])[CH2:4][O:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][CH:9]=[N:10][C:11]=2[NH2:15]
Reactant: CCOP(=O)(CSC(CO)COn1cnc2c(N)ncnc21)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1ncnc2c1ncn2OCC(CO)SCP(=O)(O)O
Reaction time: 6 h
Yield: 80.1 %

Procedure:
A solution of 9-[3-hydroxy-2-(diethoxyphosphorylmethylthio)propoxy]adenine (0.265 g, 0.67 mmol) in dry dichloromethane (20 ml) was treated with bromotrimethylsilane (1.53 g, 10 mmol) at room temperature and allowed to stand for 6 hours. The solvent was removed under reduced pressure and the residue was dissolved in methanol, before being allowed to stand for 5 minutes. The solution was evaporated to dryness under reduced pressure, re-dissolved in methanol, neutralized with AMBERLITE IR 45 OH resin and filtered and evaporated in vacuo. The residue was crystallised from water to give the title compound (180mg, 80%) as colourless crystals, m.p. 195°-97° C. λmax (H 2 O) 260nm (ε 14,000) υmax (KBr) 3320, 3110, 2920, 1720, 1595, 1550, 1490, 1460, 1405, 1340 and 1300 cm-1 ; δH [(CD3)2SO] 2.70 (2H,d, J 13.5Hz, PCH2S), 3.3 (1 H, m, CH), 3.7 (1H, m, CH ofCH2OH), 3.8 (1H, m, CH of CH2OH), 4.6 (2H, m, CH2O), 7.6 (2H, br s, exchangeable with D2O, NH2), 8.2 (1H, s, 2-H), 8.46 (1H, s, 8-H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[CH2:4][OH:5]
Reactant: Nc1cc(Cl)cc(Cl)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)cc(Cl)c1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.2 %

Procedure:
2-amino-4,6-dichlorobenzoic acid (10.0 g, 48.5 mmol) was dissolved in 50 mL of anhydrous THF in a 250 mL 2 neck round bottom flask. The solution was cooled in an ice-water bath. A solution of lithium aluminum hydride (LAH) (40 mL, 2.0 M) in THF was then added dropwise. After all of the LAH was added, the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for overnight. Water (5.1 mL) was added to the reaction mixture followed by 5.1 mL of 15% NaOH and then an additional 9.2 mL of water. The salts were filtered off and washed with THF. The filtrate was concentrated to give (2-amino-4,6-dichlorophenyl)methanol (11.1 g, wet) as a yellow solid, which was taken on to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[Cl:11])=[O:3].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]>>[Cl:11][C:5]1[CH:6]=[C:7]([O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[Cl:12])[CH:8]=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(F)cc1Cl
Reactant: Oc1ccccc1Cl
Product: CC(=O)c1ccc(Oc2ccccc2Cl)cc1Cl

Procedure:
Obtained analogously to Example 74a) starting from 2-chloro-4-fluoracetophenone and 2-chlorophenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:15](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CN=C1>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.98 mmol) in DMF (2 mL) was added TBDPS chloride (0.52 mL, 1.98 mmol) and imidazole (297 mg, 4.47 mmol) and the reaction stirred at RT for 16 h afterwhich time the reaction mixture was diluted with brine (10 mL), washed with CH2Cl2 (3×25 mL) and the organics combined and dried through a phase separation cartridge and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with EtOAc and increasing the polarity to 30% EtOAc/isohexane to obtain 4-(tert-butyl-diphenyl-silanyloxy)-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (545 mg, 62%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[O:12][CH2:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH2:2][CH2:3][CH3:4].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:38]([O:37][C:35](=[O:36])[C:34]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])[CH:7]=1)([CH3:41])[CH3:40])[CH3:39]
Reactant: CCCCc1ccc(O)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1ccc(OC(C)(C)C(=O)OCC)cc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C
Yield: 70.8 %

Procedure:
A mixture of 4-butyl-3-[2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethoxy]phenol (0.313 mmol), ethyl bromoisobutyrate (0.18 mL, 1.25 mmol) and cesium carbonate (0.41 g, 1.25 mmol) in anhydrous DMF (2 mL) was heated for 18 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 5-15% ethyl acetate/hexanes to give a yellow oil (0.12 g, 68%). 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, J=6.9, 1.7 Hz, 2H), 7.65 (q, J=7.8 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.29 (dd, J=8.1, 2.2 Hz, 1H), 4.25-4.18 (m, 4H), 2.98 (t, J=6.4 Hz, 2H), 2.48 (t, J=7.8 Hz, 2H), 2.39 (s, 3H), 1.57 (s, 6H), 1.44 (penta, J=7.6 Hz, 2H), 1.33-1.24 (m, 5H), 0.86 (t, J=7.1 Hz, 3H), MS (ES) m/e 542 (M+1).
Reaction SMILES: CCCCCC.[C:7]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)(=[O:9])[CH3:8].C(OCC)(=[O:17])C>>[S:12]1[CH:13]=[CH:14][C:10]([C:7]([CH:8]=[O:17])=[O:9])=[CH:11]1
Reactant: CCOC(C)=O
Reactant: CC(=O)c1ccsc1
Solvent: CCCCCC
Product: O=CC(=O)c1ccsc1

Procedure:
3-Acetylthiophene (20.0 g., 0.159 mol) and SeO2 (19.4 g., 0.175 mol) were dissolved 100 ml. dioxane and 8 ml. H2O by warming to 35°, then heated at reflux 16 hours. The reaction mixture was cooled, filtered and the filtrate stripped to a sludge (the hydrate of title product in crude form). The latter was distilled at reduced pressure to yield title product contaminated with about 10% starting material, 8.53 g.; tlc (5:3 hexane:ethyl acetate) Rf 0.27 (title product) and 0.59 (3-acetylthiophene). The latter was chromatographed on silica gel with 5:3 hexane:ethyl acetate is eluant. Clean product fractions were combined stripped to a solid, triturated with hexane, filtered and the solids (5.60 g.) sublimed to yield purified title product, 3.20 g.; tlc Rf 0.27 as above; sublimation point 70°/1 mm; ms: parent 141, base 111.
Reaction SMILES: [CH:1]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Na+].FC(F)=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F.N(C(C)(C)C#N)=NC(C)(C)C#N>CS(C)=O>[CH:1]([S:9]([OH:12])(=[O:10])=[O:11])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)([O-])C=Cc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: FC(F)=C(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: CS(C)=O
Product: O=S(=O)(O)C=Cc1ccccc1

Procedure:
19 g of sodium styrenesulfonate (SSNa) (available from Sigma-Aldrich Corp.) and 1 g of branched perfluorooctene (heptafluoro-3,3-bis(trifluoromethyl)-1-hexene) are fully dissolved in 0.24 L of dimethylsulfoxide (DMSO) with heating. Then, 0.1 g of azobisisobutyronitrile (AIBN) is added dropwise to the DMSO solution. The monomers are polymerized for 24 hours or more. The polymerization is carried out varying the content of the branched perfluorooctene (5, 10, and 20 wt %).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[S:9][CH:8]=1.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1>C(OCC)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([C:21]3([OH:24])[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)=[CH:8][S:9][C:10]=2[CH:15]=1
Reactant: CN1CCC(=O)CC1
Reactant: Clc1ccc2c(Br)csc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN1CCC(O)(c2csc3cc(Cl)ccc23)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A solution of 0.82 mL (0.98 mMol) n-butyllithium in 5.0 mL diethyl ether was cooled to -78° C. under a nitrogen atmosphere. To this cooled solution was added a solution of 0.22 gm (0.89 mMol) 3-bromo-6-chlorobenzothiophene in 10.0 mL diethyl ether. The reaction mixture was stirred at -78° C. for 1 hour and then to it was added dropwise a solution of 0.12 mL (0.98 mMol) 1-methyl-4-piperidone in 5.0 mL and the reaction was stirred an additional 2 hours at -78° C., then was warmed to -20° C. over 55 minutes. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate, diluted with additional diethyl ether and the phases separated. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica chromatography, eluting with toluene containing 10% ethyl acetate. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.07 gm (25%) of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.C1N2CCN(CC2)C1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].O1CCOCC1>[Cl-].[Na+].O.O>[CH3:23][O:22][C:18](=[O:21])[C:19]([CH:8]([OH:9])[C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[CH2:20]
Reactant: C=CC(=O)OC
Reactant: Cc1ccc(C=O)cn1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C(=O)OC)C(O)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 43.8 %

Procedure:
A mixture of 6-methylpyridine-3-carboxaldehyde, 97% (500 mg, 4.0 mmol, 1 eq), DABCO (458 mg, 1 eq) and methyl acrylate (1.80 ml, 5 eq) in a 1,4-dioxane (20 ml)/water (20 ml) solvent mixture was stirred at room temperature for 4 days. The resulting mixture was poured in 150 ml of brine and the organics were extracted with DCM (3×300 ml). The gathered DCM layers were dried, solvent was evaporated and the obtained crude was purified by chromatography on Biotage SP1 purification device using 25 g normal phase silica SNAP column and DCM/MeOH solvent system (gradient 1-6% of MeOH in 20 CV). Solvent from gathered fractions of appropriate composition was evaporated and the resulting crude was triturated with cyclohexane to obtain 2-[hydroxy-(6-methyl-pyridin-3-yl)-methyl]-acrylic acid methyl ester in form of white powder (375 mg, yield=43.8%, purity=95%). MS: [M+H]+=208.17 1H NMR (300 MHz; CDCl3) δ/ppm 2.55 (s, 3H), 3.11 (d, J=5.86 Hz, 1H), 3.74 (s, 3H), 5.58 (d, J=5.58 Hz, 1H), 5.87 (s, 1H), 6.38 (s, 1H), 7.15 (d, J=8.13 Hz, 1H), 7.61 (dd, J=8.13 Hz, J=2.45 Hz, 1H), 8.48 (d, J=2.45 Hz, 1H)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])=[CH:7][CH:6]=1)[CH3:2].CC(C[AlH]CC(C)C)C.CO.O>C1(C)C=CC=CC=1>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:7][CH:6]=1)[CH3:20]
Reactant: CCOC(=O)/C=C/c1ccc(C(OCC)OCC)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(OCC)c1ccc(/C=C/CO)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of (E)-ethyl 3-(4-(diethoxymethyl)phenyl)acrylate (1.400 g) in toluene (10 mL) was added DIBAH (1 M solution in toluene) (10 mL) at −20° C. under an Ar atmosphere. The mixture was stirred at −20° C. for 1 hour. To the mixture was added MeOH, and then the mixture was heated to room temperature. To the mixture was added water, and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=1/1) to afford (E)-3-[4-(diethoxymethyl)phenyl]prop-2-en-1-ol (1.120 g) as a colorless oil.
Reaction SMILES: [Na].Cl.[NH2:3]O.[F:5][C:6]([CH3:14])([CH3:13])[C:7]([O:11]C)=[CH:8][C:9]#[N:10].Cl.[OH-].[Na+]>CO.O>[F:5][C:6]([C:7]1[O:11][N:10]=[C:9]([NH2:3])[CH:8]=1)([CH3:14])[CH3:13]
Reactant: NO
Reactant: COC(=CC#N)C(C)(C)F
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: CC(C)(F)c1cc(N)no1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 12.7 %

Procedure:
To dry methanol (10 mL) at room temperature, was added portionwise sodium metal (145 mg, 6.30 mmol). After all metal had dissolved, the reaction mixture was cooled to 0° C. and hydroxylamine hydrochloride (438 mg, 6.30 mmol) was added in one portion. The reaction mixture was stirred for 15 mins before adding a solution of 4-fluoro-3-methoxy-4-methylpent-2-enenitrile (500 mg, 3.50 mmol) in dry methanol (3 mL). The mixture was heated at 70° C. for 16 h. Concentrated hydrochloric acid (0.8 mL, 9.6 mmol) was added and the reaction mixture stirred at 80° C. for 30 mins. After cooling to room temperature, the reaction was concentrated under reduced pressure to give an orange foam which was dissolved in water (50 mL) and adjusted to pH 10 using aq 1M NaOH solution. The aqueous layer was then extracted with dichloromethane (3×50 mL) and the combined organic layers were washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography eluting with 12% ethyl acetate in hexanes to 100% ethyl acetate to afford 5-(2-fluoropropan-2-yl)isoxazol-3-amine as a cream solid (64 mg, 13%). 1H NMR (300 MHz, CDCl3) δ 5.82 (s, 1H), 4.08 (brs, 2H), 1.71 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 145 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@:6]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH3:13])[C:8](=[O:21])[NH:7]1)[CH:4]=[CH2:5].[CH3:29]I>C1COCC1>[CH2:3]([C@:6]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH3:13])[C:8](=[O:21])[N:7]1[CH3:29])[CH:4]=[CH2:5]
Reactant: CI
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1C
Reaction time: 2 h
Yield: 22.6 %

Procedure:
To a suspension of NaH (84 mg, 2.1 mmol) in THF (1 mL) was added a solution of (R)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (50 mg, 0.120 mmol) in THF (5 mL) at 0° C. The resulting mixture was stirred for 2 h. Then CH3I (50 mg, 0.35 mmol) was added. The mixture was stirred for 3 h. The reaction was quenched with satd aq NH4Cl. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to afford (R)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-3-methyltetrahydropyrimidin-2(1H)-one (11.7 mg, 23%). LC-MS Method 1 tR=1.403 min, m/z=431; 1H NMR (CDCl3): δ=1.38 (d, 3H), 1.63 (m, 1H), 2.19 (m, 2H), 2.70 (m, 2H), 2.83 (m, 3H), 5.20 (m, 2H), 5.71-5.84 (m, 2H), 6.91 (m, 2H), 7.05 (m, 4H), 7.32 (m, 2H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:7])[CH3:6].[Br:18]Br>>[Br:18][C:16]1[CH:17]=[C:8]([C:5](=[O:7])[CH3:6])[CH:9]=[C:10]2[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]2
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(Br)c2c(c1)CCCC2
Temperature: 25 °C

Procedure:
To AlCl3 (9.9 g, 75 mmol) is added dropwise 6-acetyltetralin (5.25 g, 30 mmol) under mechanical stirring at RT. After 20 minutes at 70° C. the reaction is cooled to RT and treated in small portions with Br2 (5.76 g [=1.86 ml], 36 mmol) over a period of 30 minutes. After that the mixture is stirred for further 60 minutes at 85° C. After cooling down to RT and addition of ice-water (450 ml) the compound is extracted with methylene chloride and purified on silica gel using a mixture of cyclo-hexane/ethyl acetate 2/1 to 1/1 obtaining the product as a pale yellow solid.