Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)=[S:3].[CH3:33][O:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37](=O)[CH2:38]Br>>[CH3:33][O:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]1[N:1]=[C:2]([N:4]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)[CH2:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([OH:15])=[O:14])=[CH:20][CH:21]=2)[S:3][CH:38]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)C(N)=S)cc1
Product: COc1ccccc1-c1csc(N(CCc2ccc(OC(C)(C)C(=O)O)cc2)Cc2ccc(C(F)(F)F)cc2)n1

Procedure:
Similarly prepared from ethyl 2-[4-(2-{(aminocarbonothioyl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate and 2-methoxyphenacyl bromide.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].N1C=CC=CC=1.[CH3:22][CH2:23][O:24]CC.C(Cl)(=O)C>O>[C:23]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])(=[O:24])[CH3:22]
Reactant: Nc1sccc1C(=O)c1ccccc1F
Reactant: CCOCC
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: CC(=O)Nc1sccc1C(=O)c1ccccc1F

Procedure:
To a mixture of 3.90 g of 2-amino-3-(o-fluorobenzoyl)thiophene, 3.90 g of pyridine and 170 ml of anhydrous ether is added dropwise 3.90 g of acetyl chloride. Then the reaction mixture is stirred under reflux for 7 hours. After cooling, the reaction mixture is poured into water. The ether layer is separated and washed with water, and dried over sodium sulfate. The solvent is removed under reduced pressure to give an oily residure, which is crystallized from ether to give 2-acetylamino-3-(o-fluorobenzoyl)thiophene having a melting point of 143.5° - 144.5°C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([N:20]3[CH:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[CH2:23][C:22]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[N:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:40]>C(OCC)(=O)C>[ClH:40].[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[CH:24]1[N:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:15]=2)[N:21]=[C:22]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(N3CCNCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-[3-(4-BOC-piperazin-1-yl)-phenyl]-5-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (275.0 mg, 0.49 mmol) prepared in Example 215 was added to a saturated solution of hydrochloric acid in ethyl acetate (3.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 240.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[NH:20][C:19]2[CH2:18][CH2:17][N:16]([CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:15](=[O:28])[C:14]=2[C:13]=1[C:29]([F:32])([F:31])[F:30])=O)C>O1CCCC1>[CH2:26]([N:23]([CH2:24][CH3:25])[CH2:22][CH2:21][N:16]1[CH2:17][CH2:18][C:19]2[NH:20][C:12]([CH2:10][OH:9])=[C:13]([C:29]([F:30])([F:32])[F:31])[C:14]=2[C:15]1=[O:28])[CH3:27]
Reactant: CCOC(=O)c1[nH]c2c(c1C(F)(F)F)C(=O)N(CCN(CC)CC)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)CCN1CCc2[nH]c(CO)c(C(F)(F)F)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A stirred solution of lithium aluminum hydride (396 mg, 10.43 mmol) in 6 ml of anhydrous tetrahydrofuran was cooled down to 0° C. in an ice-water bath, added slowly dropwise with 5-(2-diethylamino-ethyl)-3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (1.63 g, 4.35 mmol) in 10 ml of tetrahydrofuran. Upon the completion of the addition, the reaction mixture was stirred at room temperature for 1 hour and filter through a pad of Celite. The filtrate was evaporated under reduced pressure to give the crude product 5-(2-diethylamino-ethyl)-2-hydroxymethyl-3-trifloromethyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (1.208 g, 83.4%) as a yellow oil which was used as such.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[C:5]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:4]=2[C:3]=1[F:23].[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>CN(C1C=CN=CC=1)C>[CH3:24][N:25]([CH3:30])[S:26]([N:11]1[C:5]2[C:6]3[O:10][CH:9]=[N:8][C:7]=3[C:2]([F:1])=[C:3]([F:23])[C:4]=2[N:13]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:12]1=[O:22])(=[O:28])=[O:27]
Reactant: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(I)cc1F
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Product: CN(C)S(=O)(=O)n1c(=O)n(-c2ccc(I)cc2F)c2c(F)c(F)c3ncoc3c21
Yield: 60.3 %

Procedure:
Intermediate I-20a was prepared from 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-15a: 80 mg, 0.185 mmol), N,N-dimethylaminosulfonyl chloride (41 mg, 0.277 mmol), TEA (78 mg, 0.55 mmol) and DMAP (10 mg) using procedures analogous to those described above for Intermediate I-19a to afford 60 mg of the product (60% yield). H1NMR (CDCl3, 300 MHz): δ 8.16 (s, 1H), 7.72-7.69 (m, 1H), 7.68-7.65 (m, 1H), 7.29-7.22 (m, 1H), 3.2 (s, 6H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(Cl)Cl.CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: C#CCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC#Cc1cncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromopyridine (300 mg, 0.84 mmol) in CH2Cl2 (10 mL) and NEt3 (0.4 mL) was added bis(triphenylphosphine)palladium (II) chloride (20 mg, 0.028 mmol), copper (I) iodide (2 mg) and 1-octyne (0.25 mL. 1.7 mmol). The reaction mixture was stirred and refluxed under N2 atmosphere for two days and then cooled to room temperature. After washing with aqueous 10% NaOH (1×), the organic layer was dried (MgSO4), concentrated and chromatographed (silica gel; hexane/EtOAc, 10:1 to 10:2) to afford an oil (255 mg, 79%): 1H NMR (CDCl3, 300 MHz) δ 0.88 (t, 3H, J=2.5 Hz), 1.20-1.38 (m, 4H), 1.42 (d, 4H, J=2.5 Hz), 1.44 (s, 9H), 1.90 (m, 1H), 2.00 (m, 1H), 2.40 (t, 2H, J=7.0 Hz), 3.12 (q, 4H, J=7.5 Hz), 3.32-3.44 (m, 2H), 3.90 (br, 1H), 4.08-4.20 (m, 2H), 7.10 (s, 1H), 8.08-8.30 (m, 2H); MS (CI/NH3) m/z 387 (M+H)+.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:5][C:4](=[O:10])[CH2:3][CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]12[CH2:9][CH2:8][CH2:7][CH:6]1[CH2:5][CH:4]([OH:10])[CH2:3][CH2:2]2
Reactant: O=C1CCN2CCCC2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCN2CCCC2C1
Yield: 98.4 %

Procedure:
1-Azabicyclo[4,3,0]nonan-4-one (1.0 g, 0.0072 moles) (King, F. D., J. Chem. Soc. Perkin. Trans. 1, (1986) 447) in tetrahydrofuran (50 ml) was treated with lithium aluminium hydride (0.7 g. 0.0185 moles) at ambient temperature for 18 hours. Work up in the usual way gave the title compound 1.0 g (100%). M.S. (+ve ion electrospray) m/z 142 (MH+, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:7](N)=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.N([O-])=O.[Na+].[BrH:15]>O.[Cu]Br>[Br:15][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH3:10])=[CH:5][C:6]=1[CH3:9]
Reactant: Cc1cc(C)c(N)c(Cl)n1
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(Br)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-chloro-4,6-dimethylpyridin-3-amine (2.85 g) was dissolved in hydrobromic acid (15 mL, 48% aqueous solution), and the solution was cooled to 0° C. A solution of sodium nitrite (1.51 g) in water (2 mL) was slowly added dropwise to the solution, and the mixture was stirred at 0° C. for 15 minutes. A suspension of copper(I) bromide (4.18 g) in hydrobromic acid (5 mL, 48% aqueous solution) was added dropwise to the solution, and the mixture was stirred at 0° C. for 10 minutes and then at 60° C. for one hour. The reaction mixture was cooled to room temperature, followed by extraction with ethyl acetate. The organic layer was directly subjected to an NH-silica gel pad and eluted with ethyl acetate. The resulting solution was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 0% to 30%) to give the title compound (2.97 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[C:9]([NH:11][C:12](=[NH:21])OC1C=C(C)C=CC=1)#[N:10]>C(O)(C)C>[C:9]([NH:11][C:12]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[NH:21])#[N:10]
Reactant: Cc1cccc(OC(=N)NC#N)c1
Reactant: NCc1ccccn1
Solvent: CC(C)O
Product: N#CNC(=N)NCc1ccccn1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
A mixture of 2-amino methyl pyridine (10.91 g) and 1-cyano-2-(3-tolyl)pseudourea (17.52 g) in 250 ml of isopropanol is stirred at reflux under a nitrogen atmosphere for 5 hours. The reaction mixture is allowed to cool to room temperature and the solvent is removed in vacuo. The dark green residual oil is stirred in 250 ml of diethyl ether. The resultant solid is collected and washed with ether, and ground to a paste in 100 ml of diethyl ether. The solid is filtered, washed with ether and dried in air. The solid is taken up in boiling acetone and filtered hot, concentrated in a hot plate and cooled. The precipitate is collected and recrystallized from acetone to yield 7.08 g of the cyano guanidine, MP 144° C.
Reaction SMILES: [CH3:1][C:2]([NH2:6])([C:4]#[CH:5])[CH3:3].[Li+].[NH2-].Br[CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N>[CH3:1][C:2]([CH3:3])([NH2:6])[C:4]#[C:5][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#CC(C)(C)N
Reactant: BrCCOCCCc1ccccc1
Agent: N
Agent: [Li+]
Agent: [NH2-]
Product: CC(C)(N)C#CCCOCCCc1ccccc1
Reaction time: 1.5 h
Yield: 13.8 %

Procedure:
1,1-Dimethylpropargylamine (8.5 g) was added dropwise to a suspension of lithamide [from lithium (1.7 g)] in liquid ammonia (100 ml) at -33°. The mixture was stirred for 90 min and a solution of [3-(2-bromoethoxy)propyl]benzene (21.5 g) in ER (30 ml) was added dropwise. The suspension was stirred for 4 h and ammonia was allowed to evaporate overnight. The residue was treated with H2O (100 ml) and extracted with ER (3×100 ml). The dried extract was evaporated and the residue was distilled to give the title compound as a colourless oil (3.0 g) b.p. 160°-165°/0.2 mmHg. T.l.c. (ER) Rf 0.3.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:23])[NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]O)=[CH:17][CH:16]=1.CCCCCCC>ClCCl>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:23])[NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Cl:3])=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cc1ccccc1NC(=O)Nc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5.66 ml (78.12 mmol) of thionyl chloride were added dropwise with ice cooling to a suspension of 10 g (39.06 mmol) of 4-(3-(2-methylphenyl)ureido)benzyl alcohol in 150 ml of dichloromethane. The reaction mixture was subsequently stirred at room temperature for 1.5 hours and poured onto 200 ml of n-heptane. The heptane was decanted off from the deposited oil and the oil was stirred with diisopropyl ether. The solid obtained was filtered off and washed with diisopropyl ether. Yield: 8.32 g (78%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.[OH2:14]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][C:2]1[C:3]2[C:4](=[O:13])[O:12][C:5](=[O:14])[NH:6][C:7]=2[CH:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: O
Reactant: Cc1cc(C)c2c(c1)NC(=O)C2=O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(=O)oc(=O)[nH]c2c1
Temperature: 80 °C
Yield: 31 %

Procedure:
To a stirred warm (60° C.) solution of 4,6-dimethyl-1H-indole-2,3-dione (2.0 g, 11.4 mM) in acetic acid (20 mL) was added in small portions chromium trioxide (6.6 g, 66 mM) while maintaining the temperature of the reaction mixture at 65°-70° C. The reaction mixture was then heated at 80° C. for one hour, cooled, poured into water (150 mL) and filtered to obtain the the title compound (0.67 g, 31%) as a light yellow solid; MS(CI): 192 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:27]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][N:25]=[CH:24][N:23]=4)[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(Cl)Cl>[CH3:38][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:27]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:26][N:25]=[CH:24][N:23]=4)[C:17]([C:32]([F:35])([F:33])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1cncnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncncc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.7 %

Procedure:
To a suspension of 2-(4-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyrimidin-5-yl)acetamide (29) (0.029 g, 0.060 mmol) in anhydrous methanol (2 mL) was added a 37% aq. solution of formaldehyde (0.018 mL, 0.24 mmol) under an atmosphere of nitrogen, followed by sodium triacetoxyborohydride (0.063 g, 0.30 mmol). The reaction was stirred at room temperature for 2.5 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (50 mL) and sat. aq. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL), the combined organic layers were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo to give a solid which was taken up in DCM (˜10 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice. The resulting off-white solid was suspended in DCM (5 mL) and cyclohexane was added (˜10 mL). The suspension was sonicated and the product was collected by filtration. The solid was washed with petroleum benzine 40-60° C. (5×10 mL), air-dried and subsequently dried under high-vacuum to give the title compound (30) (0.017 g, 57% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.01 (s, 1H), 8.94 (s, 1H), 8.63 (s, 1H), 8.53 (s, 1H), 7.64 (s, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.11 (s, 1H), 3.57 (s, 2H), 3.28-3.22 (m, 4H), 2.87 (d, J=11.2 Hz, 2H), 2.46-2.36 (m, 1H), 2.20 (s, 3H), 1.98 (t, J=10.6 Hz, 2H), 1.76-1.58 (m, 4H). LCMS Method C: rt 4.52 min; m/z 500.1 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)(=O)=O.[P:16]([O-:21])([O:19][CH3:20])[O:17][CH3:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:13][C:9]1[CH:8]=[C:7]([P:16](=[O:21])([O:19][CH3:20])[O:17][CH3:18])[CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Oc1cccc(Cl)c1)C(F)(F)F
Reactant: COP([O-])OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COP(=O)(OC)c1cccc(Cl)c1
Temperature: 160 °C

Procedure:
This reaction was performed using a PersonalChemistry™ microwave instrument set at normal absorbance, fixed hold time and 30 sec pre-stirring. A 10-mL reaction vial was charged with 3-chlorophenyl trifluoromethanesulfonate (0.60 g, 2.30 mmol), dimethyl phosphite (0.42 mL, 4.58 mmol) and triethylamine (0.64 mL, 4.59 mmol) in toluene (4 mL). Nitrogen was bubbled through the stirred solution for 5 min, the tetrakis(triphenylphosphine)palladium(0) (0.1 g) was added, the solution was covered with a blanket of nitrogen and sealed. The reaction mixture was heated 11 min at 160° C., then cooled to room temperature and diluted with ethyl acetate. The yellow solution washed successively with water (3×) and brine. The organic solution was dried over sodium sulfate, filtered and the solvent was removed by rotary evaporation under reduced pressure. Pure dimethyl (3-chlorophenyl)phosphonate was obtained as a colorless oil (0.27 g, 57%) by chromatography over silica gel using ethyl acetate-hexane (gradient: 5% ethyl acetate to 100%). 1H NMR (300 MHz, CDCl3) δ 7.77 (br d, J=13.7 Hz, 1H), 7.68 (ddt, J=13.0, 7.5, 1.4 Hz, 1H), 7.53 (dquint., J=8.0, 1.1 Hz, 1H), 7.38-7.45 (m, 1H), 3.79 (s, 3H), 3.75 (s, 3H) ppm; MS [M+H]+ 221, [2M+H]+ 441
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].C(Cl)Cl.[CH2:17]([NH:19][CH2:20][CH2:21]O)[CH3:18].C(N(CC)C(C)C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:17]([N:19]1[CH2:20][CH2:21][O:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[CH2:2]1)[CH3:18]
Reactant: CCNCCO
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1CCOC(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combined 2-Bromo-1-(4-nitro-phenyl)-ethanone (5.0 g, 0.020 mol) with Methylene chloride (100 mL, 2 mol) and treated with 2-Ethylamino-ethanol (2.0 mL, 0.020 mol) and N,N-Diisopropylethylamine (3.6 mL, 0.021 mol), stirred at rt, 3 h. Treated the mixture with Triethylsilane (10.33 mL, 0.06468 mol) and then Trifluoroacetic Acid (52.5 mL, 0.681 mol) and heated to 40° C. and stirred under nitrogen overnight. Concentrated and partitioned between ice/water and heptane, stirred vigorously for 10 min. Decanted off the heptane to remove silyl byproducts, repeated. Basified with solid K2CO3. Extracted with EtOAc, the organics were washed with brine, dried (MgSO4), filtered and concentrated onto Celite and purified by ISCO chromatography (80 g, SiO2, gradient elution: 100% Hex to 100% EtOAc to 10% MeOH/EtOac), (+/−)-4-Ethyl-2-(4-nitro-phenyl)-morpholine was isolated as red waxy solid (2.45 grams). 1H-NMR (CDCl3) δ 8.22 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.8 Hz, 2H), 4.69 (dd, J=10.5, 2.3 Hz, 1H), 4.10 (dd, J=11.5, 2.0, 1H), 3.90-3.84 (m, 1H), 4.11-4.08 (m, 1H), 3.00 (d, J=11.5 Hz, 1H), 2.87 (d, J=9.9 Hz, 1H), 2.48 (dd, J=7.2, 14.4 Hz, 2H), 2.27-2.20 (m, 1H), 1.99 (t, J=10.7 Hz, 1H), 1.13 (t, J=7.2 Hz, 3H); LC/MS (ESI+): 237 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5](F)[CH:4]=1)#[N:2].C(=O)([O-])[O-:13].[K+].[K+]>CN(C)C=O.O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([OH:13])[CH:4]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(C=O)c(F)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C=O)c(O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-cyano-2-fluorobenzaldehyde (11.73 g, 78.7 mmol) and potassium carbonate (14.12 g, 102.3 mmol) was dissolved in dry dimethylformamide (35 ml). To this was added water (6.63 ml, 368.5 mmol). The resulting solution was heated to 90° C. with stirring. A further equivalent of water (1.42 ml) was added after 2 hours, then a further two equivalents of water (2.84 ml) 1 hour later. The resulting solution was left overnight. After 24 hours a further 2 equivalents of water (2.84 ml) was added, then heated for a further 2 hours at 90° C. The cooled solution was diluted with water to form a murky yellow solution. The solid precipitate was filtered. The remaining yellow filtrate was acidified with concentrated hydrochloric acid to produce a yellow solid. This was filtered, then dried at 40° C. overnight to give 4-cyano-2-hydroxybenzaldehyde as a yellow solid.
Reaction SMILES: C(OC(OCC)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)C.C([Li])CCC.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[C:20]=1[CH:21]=[O:22]>O1CCCC1.CCCCCC>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH3:28])[C:20]=1[CH:21]([C:6]1[NH:5][CH:9]=[CH:8][N:7]=1)[OH:22]
Reactant: CCc1cccc(Cl)c1C=O
Reactant: CCOC(OCC)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1cccc(Cl)c1C(O)c1ncc[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of 1.60 ml (9.79 mmol) 1-(diethoxymethyl)imidazole in 6 ml tetrahydrofuran at −78° C. was added dropwise 6.67 ml (10.7 mmol) of a 1.6 M solution of n-butyllithium in hexane. The resulting solution of 2-(1-diethoxymethyl-1H-imidazol-2-yl)-lithium was stirred at −78° C., and then added dropwise to a solution of 1.50 g (8.90 mmol) 2-chloro-6-ethyl-benzaldehyde in 6 ml tetrahydrofuran at 0° C. The reaction mixture was then stirred at 0° C. for 30 min and at room temperature for 1 h, before being quenched by dropwise addition of 1 M aqueous hydrochloric acid. The mixture was made basic by addition of aqueous sodium bicarbonbate solution and diluted with ethyl acetate. The phases were separated and the organic phase was washed with saturated brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 2.02 g (96%) of the title compound as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH:29]2OCC[O:30]2)=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[K+].[K+].N1C=CN=C1.C([Si](Cl)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH:29]=[O:30])=[CH:22][CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1ccc(CCCC2OCCO2)cc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1ccc(CCCC=O)cc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a solution of 5.5 g (11.9 mmol) of the dioxolane 171 in 40 mL of THF at room temperature was added 40 mL of 4.0N HCl and the resulting solution was allowed to stir for 1 h. The mixture was neutralized with solid K2CO3, extracted with ethyl acetate and concentrated. The crude mixture was dissolved into 25 mL of CH2Cl2 to which was added 600 mg (8.8 mmol) of imidazole and 1.9 mL (7.3 mmol) of tert-butylchlorodiphenyl silane. The resulting mixture was allowed to stir overnight at room temperature and was then poured into 0.5N HCl and extracted with ethyl acetate. The organics were dried over MgSO4, filtered and concentrated. Flash chromatography (elution with 8% ethyl acetate in hexane) gave 2.12 g of the aldehyde 172 as an oil. 1H NMR consistent with the product.