Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH:26]=4)=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.[OH-:34].[Na+].OO>C1COCC1.O>[OH:34][CH:22]1[CH:21]([C:18]2[CH:17]=[CH:16][C:15]([N:13]3[CH:14]=[C:10]([C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][N:2]=4)[N:11]=[N:12]3)=[CH:20][CH:19]=2)[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)CC1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)C(O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22 %

Procedure:
To a stirred solution of borane-methyl sulfide complex (587 μl of a 2.0 M solution in THF; 1.18 mmol; 1.3 eq.) in THF (6.0 mL) maintained at 0° C. under nitrogen atmosphere, was added dropwise a solution of tert-butyl 4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (400 mg; 0.90 mmol; 1.0 eq.) in THF (6.0 mL). The reaction mixture was stirred at RT for 12 h. Further borane-methyl sulfide complex (135 μl of a 2.00 M solution in THF; 0.27 mmol; 0.3 eq.) was added and the reaction mixture was stirred at RT for 1 more hour. The reaction mixture was then cooled down to 0° C. before the dropwise addition of NaOH (3.6 mL) followed by hydrogen peroxide (615 μl). It was then allowed to warm to RT and stir O/N. The reaction mixture was then diluted with water and extracted with DCM (four times). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (EtOAc:heptanes, gradient from 90:10 to 40:60) to give the title compound as a white foam (90 mg, 22%). HPLC (max plot) 96.4%; Rt % 4.16 min. UPLC/MS: (MS+) 461.4, (MS−) 459.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH:9]=[O:10].[CH3:11][Mg]Cl.Cl.[Mg]>C1COCC1.O>[CH3:11][CH:9]([OH:10])[CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: C[Mg]Cl
Reactant: O=CCCc1ccccn1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)CCc1ccccn1
Reaction time: 1 h

Procedure:
Dimethyl sulphoxide (3.3 ml) was added dropwise to a solution of oxalyl chloride (3.9 ml) in dichloromethane (25 ml) at -78° under nitrogen. After gas evolution had ceased (5 min) a solution of 2-pyridinepropanol (4.0 g) in dichloromethane (20 ml) was added over 5 min and the solution stirred at -78° for 20 min. Triethylamine (5 ml) was added dropwise to the solution, then the resulting dark green mixture warmed to 20° and washed with 2M sodium carbonate solution (20 ml). The organic phase was dried and evaporated in vacuo to give 2-pyridinepropanal. This aldehyde was immediately dissolved in THF (30 ml) and added dropwise to a 3M solution of methylmagnesium chloride in THF (20 ml) at 0°-5° under nitrogen. After 1 h, water (10 ml) was cautiously added followed by sufficient 2M hydrochloric acid to dissolve all the magnesium residues (resulting pH~7 ). The solution was extracted with dichloromethane (3×30 ml) and the organic extracts dried and evaporated in vacuo to a dark oil. Kugelrohr bulb to bulb distillation (b.p. 130°-135°/0.7 mm) afforded the title compound as a pale yellow oil (0.91 g), t.l.c. ethyl acetate Rf 0.17.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[F:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[NH:19][NH2:20]>C(O)(=O)C>[F:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[NH:19][N:20]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NNc1ccncc1F
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1Nc1ccncc1F
Yield: 126.9 %

Procedure:
To a stirred solution of phthalic anhydride (1.76 g) in acetic acid (45 ml), 3-fluoro-4-hydrazinopyridine (1.52 g) was added. The reaction mixture was heated under reflux for 1 hr and concentrated in vacuo to give 3.88 g of 2-(3-fluoro-pyridin-4-ylamino)isoindole-1,3-dione. To a stirred solution of 2-(3-fluoropyridin-4-ylamino)isoindole-1,3-dione (3.88 g) in tetrahydrofuran (125 ml) at 0° C., lithium aluminum hydride (2.86 g) was added. The reaction mixture was allowed to warm to ambient temperature and was stirred for 1 day. Sodium sulfate decahydrate was added, and the mixture was filtered. The filtrate was concentrated in vacuo. The residue was chromatographed on a silica gel eluting with ethyl acetate. The appropriate fractions were collected and concentrated to yield 1.28 g (37%) of product free base. A portion of the free base was dissolved in methanol, and ethereal hydrogen chloride was added. The precipitate was collected and recrystallized from methanol to yield 0.200 g of product, mp 200-202° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([C:22](O)=[O:23])=[CH:19][C:18]=3[CH3:25])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([CH3:28])[C:22]([C:20]1[S:21][C:17]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:18]([CH3:25])[CH:19]=1)=[O:23]
Reactant: CNC
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(C(=O)O)cc3C)c(C)nc12
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C(=O)N(C)C)cc3C)c(C)nc12
Yield: 100 %

Procedure:
Using a procedure analogous to Example 23B, 5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiophene-2-carboxylic acid (151 mg, 0.42 mmol) and 2.0 M dimethylamine (2.0 mL, 4 mmol) give the title compound (161 mg, 0.42 mmol, 100%). 1H NMR (CDCl3): δ 0.89 (t, J=7.4 Hz, 6H), 1.75-1.94 (m, 4H), 2.14 (s, 3H), 2.51 (s, 3H), 2.53 (s, 3H), 3.15-3.50 (m, 7H), 6.72 (s, 1H), 7.30 (s, 1H). ES-MS (m/z): calcd for C21H28N4OS (M+H)+: 385.6 found: 385.3.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=4[Cl:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:26]([OH:30])[CH2:27][CH2:28][CH3:29])=[CH:6][CH:5]=1.[CH3:31]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=4[Cl:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:26]([O:30][CH3:31])[CH2:27][CH2:28][CH3:29])=[CH:6][CH:5]=1
Reactant: CCCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 60.6 %

Procedure:
Sodium hydride (60% in oil, 7.6 mg, 0.190 mmol) was added to a stirred solution of 1-[9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]butan-1-ol (69.5 mg, 0.158 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature. After stirring 5 min, methyl iodide (33.6 mg, 0.237 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (43.4 mg, 0.0958 mmol, 61%).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH2:12][CH3:13])([O-:11])=[O:10]>>[N+:9]([CH:12]([CH3:13])[CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:8])([O-:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: CC[N+](=O)[O-]
Product: CC(C(O)c1ccccc1)[N+](=O)[O-]

Procedure:
In a preferred embodiment, a method for producing 2-nitro-1-phenyl-1-propanol is provided. This method comprises reacting benzaldehyde with nitroethane in the presence of an amine catalyst. The 2-nitro-1-phenyl-1-propanol produced by this reaction has a (1R*,2S*) stereoisomer and a (1R*,2R*) stereoisomer. The preferred (1R*,2S*) stereoisomer makes up greater than about 50% of the 2-nitro-1-phenyl-1-propanol. Reduction of this nitro-alcohol produces dl-norephedrine in high yield.
Reaction SMILES: [OH-].[K+].N([CH:10]([C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)P(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[N+:36]([C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][CH:40]=1)([O-:38])=[O:37]>CO.C1COCC1>[N+:36]([C:39]1[CH:40]=[CH:41][C:42]([C:43](=[O:44])[CH2:10][C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=2)=[CH:45][CH:46]=1)([O-:38])=[O:37]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(C(Nc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A solution of KOH (7.56 g, 0.13 mol) in MeOH (75 ml) was added to the phosphonate ester 33 (62.1 g, 0.13 mol) in THF (400 ml) at -78° C. for 0.5 hour and p-nitrobenzaldehyde (20.3 g, 0.13 mol) in 200 ml of THF was added over 0.5 hour. The reaction was warmed to room temperature and stirred an additional 2 hours. THF was removed under reduced pressure. The residue was taken up in EtOAc and washed twice with 5% aqueous NaHCO3 and once with brine. The ethyl acetate was removed under reduced pressure. The dark red enemine was dissolved in CH3OH (600 ml) and concentrated HCl (0.2 ml) was added. The solution was stirred for 1 hour at room temperature and diluted with H2O (500 ml). The solid was filtered, washed with ether and dried to afford 34 (35.6 g, 82.0%), m.p. 131°-133° C.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.[OH-].[Na+]>O.C(O)C>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:16])[CH:15]=[CH:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[F:17])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=Cc1ccccc1F
Reactant: CC(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1ccc(C(=O)C=Cc2ccccc2F)c(Cl)c1Cl
Yield: 54.9 %

Procedure:
To 500 ml of ethanol was added [2,3-dichloro-4-(1-oxo-ethyl)phenoxy]acetic acid (19.73 g, 0.075 mole), 2-fluorobenzaldehyde (13.63 g, 0.11 mole), sodium hydroxide (10 g, 0.25 mole) in 20 ml of water and 50 ml of ethanol with stirring under nitrogen. The reaction mixture was refluxed for a total of 11/2 hours. The reaction mixture was cooled, filtered, the gelatineous solid dispersed in water acidified with hydrochloric acid, stirred, filtered and washed with water. The residue was extracted with methylene chloride and ethyl acetate, washed with water, and concentrated under reduced pressure to give 15.2 g of [2,3-dichloro-4-(3-(2-fluorophenyl)-1-oxo-2-propenyl)phenoxy]acetic acid which melted at 191°-194° C. after purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4](=[O:31])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].[C:34]([C:36]1[CH:37]=[C:38]([N:44]2CCNCC2)[CH:39]=[CH:40][C:41]=1[C:42]#[N:43])#[N:35]>>[C:34]([C:36]1[CH:37]=[C:38]([N:44]2[CH2:2][CH2:1][N:3]([C:4](=[O:31])[CH:5]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:6]([NH:8][S:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=3)(=[O:10])=[O:11])=[O:7])[CH2:32][CH2:33]2)[CH:39]=[CH:40][C:41]=1[C:42]#[N:43])#[N:35]
Reactant: N#Cc1ccc(N2CCNCC2)cc1C#N
Reactant: CCN(CC)C(=O)C(Cc1ccc(OC)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: COc1ccc(CC(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(c3ccc(C#N)c(C#N)c3)CC2)cc1
Yield: 67.3 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (550 mg) obtained in Example 112 (4) and N-(3,4-dicyanophenyl)piperazine (282 mg). This was purified by silica gel column chromatography to give the title compound (480 mg) as a yellow powder.
Reaction SMILES: [CH2:1]1[C:4]2(OCC[O:5]2)[CH2:3][CH:2]1[N:9]1[CH:13]=[C:12]([I:14])[CH:11]=[N:10]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>O1CCOCC1.O>[I:14][C:12]1[CH:11]=[N:10][N:9]([CH:2]2[CH2:1][C:4](=[O:5])[CH2:3]2)[CH:13]=1
Reactant: Ic1cnn(C2CC3(C2)OCCO3)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC(n2cc(I)cn2)C1
Yield: 85.5 %

Procedure:
A solution of 1-(5,8-dioxa-spiro[3.4]oct-2-yl)-4-iodo-1H-pyrazole (Compound 100E, 8.8 g, 29 mmol) and pyridinium p-toluenesulfonate (21 g, 87 mmol) in dioxane-water (140 mL of 1:1 mixture) was stirred at 85° C. for 12 h. The reaction mixture was concentrated and diluted with ethyl acetate (100 mL), the organic layer was washed with water (2×50 mL), dried (Na2SO4) and concentrated to give 6.5 g (yield: 86%) of 3-(4-iodo-1H-pyrazol-1-yl)cyclobutanone. 1H NMR (CDCl3, 300 MHz): δ=3.53-3.57 (m, 2H), 3.73-3.77 (m, 2H), 5.0-5.02 (m, 1H), 7.56 (s, 1H), 7.58 (s, 1H).
Reaction SMILES: C(C1N(C[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])C(/C(/C)=C(\CC2C=CSC=2)/C(O)=O)=CN=1)CCC.[CH2:30]([C:34]1[N:35]([CH2:56]OCC[Si](C)(C)C)[C:36](/[C:39](/[CH2:52][CH2:53][CH2:54][CH3:55])=[C:40](\[CH2:46][C:47]2[S:48][CH:49]=[CH:50][CH:51]=2)/[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:37][N:38]=1)[CH2:31][CH2:32][CH3:33]>>[CH2:30]([C:34]1[N:35]([CH2:56][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:36](/[C:39](/[CH2:52][CH2:53][CH2:54][CH3:55])=[C:40](\[CH2:46][C:47]2[S:48][CH:49]=[CH:50][CH:51]=2)/[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:37][N:38]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCc1ncc(/C(C)=C(\Cc2ccsc2)C(=O)O)n1Cc1ccccc1Cl
Reactant: CCCC/C(=C(/Cc1cccs1)C(=O)OCC)c1cnc(CCCC)n1COCC[Si](C)(C)C
Product: CCCC/C(=C(/Cc1cccs1)C(=O)OCC)c1cnc(CCCC)n1Cc1ccccc1Cl

Procedure:
The procedure of Example 6, Method B (iv, v) is followed using ethyl (E)-3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}-1H-imidazol-5-yl]-2-(2-thienyl)methyl-2heptenoate in in place of ethyl (E)-3-[2-n-butyl-1-{(trimethylsilyl) ethoxymethyl}-1H-imidazol-5-yl]-2-(5-methyl-2-furyl)methyl-2-heptanoate to give the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Br[CH:29]([CH3:35])[C:30](OCC)=[O:31].CN(C)C=O>O>[CH3:35][CH:29]1[S:27][C:25]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[N:4]2)=[N:26][C:30]1=[O:31]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Reactant: CCOC(=O)C(C)Br
Solvent: O
Solvent: CN(C)C=O
Product: CC1SC(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)=NC1=O
Temperature: 85 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A mixture of 1.00 g (2.60 mmol) of the starting material I, 0.94 g (5.19 mmol) of ethyl 2-bromopropionate and 10 ml of dimethylformamide was stirred at 80-90° C. for 2 h. After diluting with water the obtained crude product was purified by refluxing in 15 ml of ethanol to yield 1.08 g (95%) of the title compound; Mp.: 213-214° C.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[O:5][CH2:4]1.[F:6][C:7]([F:15])([F:14])[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:6][C:7]([F:15])([F:14])[C:8]1([C:10]([F:13])([F:12])[F:11])[O:5][CH:3]([CH:2]=[CH2:1])[CH2:4][O:9]1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: C=CC1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Product: C=CC1COC(C(F)(F)F)(C(F)(F)F)O1
Temperature: 120 °C
Yield: 12.1 %

Procedure:
Butadiene monoepoxide (9.8 g, 0.14 mole, Aldrich Chemical Co.) was mixed with hexafluoroacetone (50 g, 0.30 mole) in a 210 ml Hastelloy®C shaker tube in the presence of tetrabutylammonium bromide (0.12 g) and water (0.12 g). The tube was sealed and heated at 80° C. for 1 hour, 100° C. for 1 hour and 120° C. for 6 hours. The product mixture was distilled to afford the desired 2,2-bis(trifluoromethyl)-4-vinyl-1,3-dioxolane, 4.0 g (12.1% yield), as a clear, colorless liquid. Bp. 78°-80° C. 1H-NMR (CDCl3): δ 5.84 (m, 1H), 5.48 (m, 2H), 4.88 (dd, J=6.6, 5.4 Hz, 1H), 4.46 (t, J=6.6 Hz, 1H), 3.87 (t, J=6.6 Hz, 1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH:4]=C1C=CC=CC1[PH+](C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][C:37]1[CH:50]=[CH:49][CH:48]=[CH:47][C:38]=1[C:39]([C:41]1[O:46][CH2:45][CH2:44][O:43][N:42]=1)=O>O1CCCC1>[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][C:37]1[CH:50]=[CH:49][CH:48]=[CH:47][C:38]=1[C:39]([C:41]1[O:46][CH2:45][CH2:44][O:43][N:42]=1)=[CH:2][O:3][CH3:4]
Reactant: O=C(C1=NOCCO1)c1ccccc1OC1CCCCO1
Reactant: COC=C1C=CC=CC1[PH+](c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=C(C1=NOCCO1)c1ccccc1OC1CCCCO1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 63 %

Procedure:
A mixture of 31.2 g (0.091 mol) of methoxymethylene-triphenyl-phosphonium chloride and 10.2 g (0.091 mol) of potassium tert-butoxide in 100 ml of tetrahydrofuran is stirred for 20 minutes at 20° C. A solution of 13.3 g (0.0457 mol) of 3-[2-(tetrahydropyran-2-yloxy)-benzoyl]-5,6-dihydro-1,4,2-dioxazine in 100 ml of tetrahydrofuran is then added, and the mixture is refluxed at the boil for 12 hours. The mixture is concentrated under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic phase is separated off and dried over sodium sulphate. The residue is chromatographed on silica gel using cyclohexane/ethyl acetate (1:1). 9.2 g (63% of theory) of 3-{1-[2-(tetrahydropyran-2-yloxy)-phenyl]-2-methoxyethen-1-yl}-5,6-dihydro-1,4,2-dioxazine are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2.[CH:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>O1CCCC1>[C:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2)#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=Cc1ccc2cc(Br)ccc2n1
Reactant: C#CCCCCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCC#Cc1ccc2nc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
A solution of 6-bromo-2-quinolinecarboxaldehyde (18.9 g), 1-decyne (12.2 g) and triethylamine (24.3 g) in dry tetrahydrofuran (300 ml) was chilled to 5° C. and degassed, under nitrogen. bis(Triphenylphosphine)palladium (II) chloride (0.56 g) and copper (I) iodide (0.08 g) were added to the reaction mixture, which was degassed and stirred under nitrogen at room temperature for 30 mins, and then heated at 40° C. for 19 hrs. The mixture was cooled to room temperature, the precipitate was filtered, and the filter cake was washed with ethyl acetate, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with heptane to heptane:2% ethyl acetate. The appropriate fractions were collected and evaporated. A 2 g-portion of the residue (23.4 g) was chromatographed, eluting with hexane:dichloromethane/2:1 give 1.3 g (64.0%) of product, mp 46.5-47.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=[O:15])[C:12]([C:16]#[N:17])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.Br[CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:10]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[N:14][C:13]([O:15][CH2:26][CH2:27][N:28]3[C:29](=[O:38])[C:30]4[C:31](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:33])=[C:12]([CH:11]=2)[C:16]#[N:17])=[CH:23][CH:22]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCCN1C(=O)c2ccccc2C1=O
Temperature: 70 °C

Procedure:
To the product of Step B Example 19 (600 mg, 1.597 mmol) was added N-(2-bromoethyl)-phthalimide (690 mg, 2.715 mmol), K2CO3 (331 mg, 2.396 mmol) and DMF (8 mL). The mixture was heated to 70° C. for 20 hours. The mixture was filtered, concentrated and passed through a short plug of silica gel eluting with 33% ethyl acetate/hexane. The partially purified material was carried on without further purification. MS (electrospray) m/e 547.8 MH+ (retention time=4.4 min LC/MS).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[NH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[CH2:31][CH2:32][O:33][CH3:34].[F-].[Cs+]>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24]([O:29][CH2:31][CH2:32][O:33][CH3:34])=[N:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COCCBr
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc[nH]c3=O)cc1-2
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COCCOc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Temperature: 80 °C
Yield: 6 %

Procedure:
To 330 (0.075 g, 0.18 mmol) in DMF (2 mL) was added 1-bromo-2-methoxyethane (0.1 mL, 0.55 mmol) and cesium fluoride (0.084 g, 0.55 mmol). The reaction mixture was allowed to stir and heat at 80° C. for 2 days while monitoring by LCMS. To the reaction mixture was added bromo-2-methoxyethane (1 mL, 7.2 mmol) and cesium fluoride (1.0 g, 6.6 mmol). The reaction mixture was allowed to stir and heat at 80° C. for 2 days before cooling, concentrating under reduced pressure, and diluting with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure. The crude material was dissolved in DMF and purified by reverse phase HPLC to provide 478 (5 mg, 6%). 1H NMR (400 MHz, DMSO) δ 8.60 (d, J=2.3, 1H), 8.16 (dd, J=4.9, 1.8, 1H), 8.10 (s, 1H), 7.80 (dd, J=7.4, 1.8, 1H), 7.59 (dd, J=8.4, 2.3, 1H), 7.13 (dd, J=7.7, 5.0, 2H), 5.73 (dt, J=13.1, 6.6, 1H), 4.51-4.38 (m, 4H), 3.70-3.58 (m, 2H), 3.48 (t, J=5.0, 2H), 3.18 (d, J=14.6, 3H), 1.55-1.46 (m, 6H). MS (ESI(+)): m/z 464.1 (M+H)