Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[O:16])[O:4][CH2:5][CH:6]=[C:7]([F:15])[S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[CH3:17][N:2]([CH3:1])[C:3](=[O:16])[O:4][CH2:5]/[CH:6]=[C:7](\[F:15])/[S:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:26]
Reactant: CCCCCCSC(F)=CCOC(=O)N(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCS(=O)/C(F)=C/COC(=O)N(C)C
Reaction time: 0.25 h

Procedure:
To the above carbamate is added a solution of m-chloroperbenzoic acid (431 mg, 2.5 mmol) in 10 ml of methylene chloride. After 15 min, the reaction mixture is extracted with KHCO3 and Na2SO3 and stripped. The product is purified by prep. TLC eluting with ethyl acetate (neat). The upper band is collected to give (E)-3-fluoro-3-hexylsulfinyl-2-propenyl dimethylcarbamate (cpd. 28, Table A).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.Br[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][N:16]3[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Brc1ccncc1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3cc[nH]c3c2)c1
Agent: Cl
Product: O=[N+]([O-])c1cccc(-c2ccc3ccn(-c4ccncc4)c3c2)c1

Procedure:
The target compound was prepared as in Example 1 using 6-(3-nitrophenyl)-1H-indole (98 mg, 0.412 mmol) and 4-bromopyridine hydrochloride (88 mg, 0.453 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][NH:10][C:9](=O)[C:8]=2[CH:13]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:16])=O.C(N(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:16][C:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[S:11][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]sc2ccc([N+](=O)[O-])cc12
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: O=[N+]([O-])c1ccc2snc(Cl)c2c1
Temperature: 109 °C
Reaction time: 8 h

Procedure:
A mixture of 5-nitro-1,2-benzisothiazol-3(2H)-one (10.0 g, 0.0510 mol), phosphorus oxychloride (40.0 mL, 0.429 mol) and tributylamine (12.0 mL, 0.050 mol) is heated at 103-115° C. for six hours, stirred at room temperature overnight, and poured into an ice-water mixture. The resultant aqueous mixture is extracted with methylene chloride. The combined organic extracts are washed sequentially with water and saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a gum. Column chromatography of the gum using silica gel and methylene chloride gives the title product as an orange-yellow solid which is identified by NMR spectral analysis.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17](=[O:32])[CH:18]=[N:19][O:20][CH2:21][C:22]1[CH2:27][C:26]([CH3:28])=[C:25]([CH3:29])[CH2:24][C:23]=1[CH2:30]Cl>>[CH3:15][O:16][C:17](=[O:32])[CH:18]=[N:19][O:20][CH2:21][C:22]1[CH2:27][C:26]([CH3:28])=[C:25]([CH3:29])[CH2:24][C:23]=1[CH2:30][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[CH3:8]
Reactant: Cc1ccccc1O
Reactant: COC(=O)C=NOCC1=C(CCl)CC(C)=C(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)C=NOCC1=C(COc2ccccc2C)CC(C)=C(C)C1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
20 g of o-cresol and 40 g of potassium carbonate are added to a solution of 27.5 g of methyl(2-chloromethyl-4,5-dimethylcyclohexa-1,4-dienyl)methoxyiminoacetate. The mixture is now heated for 14 hours at 65°, cooled to room temperature and filtered with suction, and the filtrate is evaporated. The residue is taken up in 150 ml of ethyl acetate, the mixture is washed with potassium carbonate solution and filtered with suction, and the filtrate is evaporated. In this manner, 34 g of the title compound are obtained as a pale brown oil.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=34)=[N:8][CH:9]=2)[N:4]1[C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.[C:29]([CH2:31][C:32](ON1C(=O)CCC1=O)=[O:33])#[N:30]>CN(C=O)C>[C:29]([CH2:31][C:32]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:23]([N:4]2[C:3](=[O:2])[NH:11][C:10]3[C:5]2=[N:6][C:7]([C:12]2[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=24)=[N:8][CH:9]=3)[CH2:24]1)=[O:33])#[N:30]
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
To a solution of the compound obtained in example 6 (45 mg, 0.095 mmol) in anhydrous DMF (3 mL), 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (69 mg, 0.38 mmol) and anhydrous TEA (0.09 mL, 0.665 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO2 aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was flash chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 11.7 mg of the desired compound (29% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C@@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8]Cl.[NH4+:19].[OH-].CCO.C(O)(=O)/C=C\C(O)=O>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C@@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:8][NH2:19]
Reactant: Fc1cccc(O[C@H](CCCl)c2ccccc2)c1
Reactant: [NH4+]
Agent: O=C(O)/C=C\C(=O)O
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCC[C@@H](Oc1cccc(F)c1)c1ccccc1

Procedure:
A solution of (R)-3-(3-fluorophenoxy)-3-phenylpropyl chloride (0.971 g, 3.96 mmol), conc. NH4OH (30 mL) and EtOH (20 mL) were shaken at 90° C. on a Parr apparatus (50-90 psig) for 18 h. The mixture was then evaporated under vacuum and the residue was dissolved in Et2O (100 mL) and washed with H2O (2×25 mL). The organic layer was dried (anh. Na2SO4), filtered, and evaporated under vacuum to provide a yellow oil. This material was then dissolved in EtOAc (50 mL) and filtered. A solution of maleic acid (0.272 g, 2.6 mmol, 0.93 equiv) dissolved in hot EtOAc (5 mL) was added to precipitate the maleate salt (519 mg, 53.5%) as a white solid: TLC Rf 0.25 (1% MeOH—CHCl3); GC, tr 7.37 min; MS, m/z 245 (M+). The synthesis of Compound 187 was accomplished as follows.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].C[O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[CH2:36][NH:35][CH2:34][CH2:33]2>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([C:7]([S:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH:34]2[CH2:33][CH2:32][C:37]3[CH:38]=[C:39]4[O:40][CH2:41][O:29][C:30]4=[CH:31][C:36]=3[NH:35]2)[C:8]#[N:9])[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(C(C#N)(CCCCCCl)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(cc1OC)CNCC2
Product: COc1ccc(C(C#N)(CCCCCC2CCc3cc4c(cc3N2)OCO4)Sc2ccc(C)cc2)cc1OC
Yield: 60.9 %

Procedure:
The procedure of Example 3 is repeated using 0.854 g of α-(5-chloropentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]-benzeneacetonitrile and 0.677 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline. This affords 0.701 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.O1CCCC1>O>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:17][CH:14]2[CH2:16][CH2:15]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(S(=O)(=O)NC2CC2)c1
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
A mixture of 2.0 g 3-nitrobenzene sulfonyl chloride, 1.8 g cyclopropyl amine and 50 mL tetrahydrofuran was stirred for 30 minutes under ice-cooling. Water was added to the mixture which was then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, then the residue was dissolved in 100 mL solvent mixture of tetrahydrofuran and methanol, 50 mg of 10% palladium-carbon was added thereto, and the mixture was hydrogenated at ordinary pressure for 12 hours. The reaction mixture was filtered through Celite, and the solvent was evaporated, whereby 1.5 g of the title compound was obtained as a pale yellow solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10]C)=O.Cl.[Cl:13][CH:14]([CH3:18])[C:15](=[NH:17])[NH2:16].C(N(CC)CC)C>>[Cl:13][CH:14]([C:15]1[NH:17][C:8](=[O:10])[C:3]2[CH2:4][O:5][CH2:6][CH2:7][C:2]=2[N:16]=1)[CH3:18]
Reactant: CC(Cl)C(=N)N
Reactant: COC(=O)C1COCCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(Cl)c1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 103.5 %

Procedure:
A mixture of methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (1.0 g, 6.3 mmol), 2-chloropropanimidamide hydrochloride (0.9 g, 6.3 mmol), and triethylamine (3.52 mL, 25.4 mmol) was stirred at ambient temperature for 24 h. The mixture was concentrated in vacuo to give the title compound (1.4 g), which was used directly to the next step without further purification. MS m/z 215.2 (M+1), retention time=1.27 min.
Reaction SMILES: [P:1]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([O:3][CH2:4][C:5]([NH2:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])=[O:2].[CH:24]([C:27]1[CH:28]=[CH:29][C:30]2[C:35]([NH:36][C:37]3[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=3[S:46][C:47]3[CH:52]=[CH:51][C:50]([NH:53][C:54]([O:56][CH3:57])=[O:55])=[CH:49][CH:48]=3)[C:40](O)=[O:41])=[N:34][CH:33]=[N:32][C:31]=2[N:58]=1)([CH3:26])[CH3:25]>>[C:20]([O:19][P:1]([O:3][CH2:4][C:5]([NH:13][C:40]([C:39]1[CH:43]=[CH:44][C:45]([S:46][C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:54](=[O:55])[O:56][CH3:57])=[CH:51][CH:52]=2)=[C:37]([NH:36][C:35]2[C:30]3[CH:29]=[CH:28][C:27]([CH:24]([CH3:26])[CH3:25])=[N:58][C:31]=3[N:32]=[CH:33][N:34]=2)[CH:38]=1)=[O:41])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:2])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OP(=O)(OCC(C)(N)c1ccccc1)OC(C)(C)C
Reactant: COC(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Product: COC(=O)Nc1ccc(Sc2ccc(C(=O)NC(C)(COP(=O)(OC(C)(C)C)OC(C)(C)C)c3ccccc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Yield: 43 %

Procedure:
The title compound was prepared (yield 43%) by the procedure of Example 441E substituting the product of Example 442C for the product of Example 441D.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C1(C)C=CC=CC=1.[CH3:18][O:19][C:20]([C:22]1[N:23]=[N:24][C:25]([C:32](OC)=[O:33])=[CH:26][C:27]=1[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:21]>C(Cl)Cl>[CH3:18][O:19][C:20]([C:22]1[N:23]=[N:24][C:25]([C:32]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:33])=[CH:26][C:27]=1[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:21]
Reactant: C1CCNCC1
Reactant: COC(=O)c1cc(CC(C)C)c(C(=O)OC)nn1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1nnc(C(=O)N2CCCCC2)cc1CC(C)C
Temperature: 25 °C
Yield: 54.5 %

Procedure:
An oven dried, nitrogen cooled two-necked 25 mL round bottom flask was charged with a solution of 78 μL piperidine (0.793 mmol, 68 mg) in 4.0 mL anhydrous DCM. Trimethyl aluminum was added slowly (2.0M/toluene, 436 μL, 0.872 mmol). The resulting mixture was stirred for twenty minutes at room temperature. To this solution was added 200 mg of the diester 3 (0.793 mmol) dissolved in 2.0 mL anhydrous DCM. The flask was sealed and heated to 41° C. for 15 hours. The reaction was allowed to cool to room temperature and quenched with slow addition of 1M HCl. The product was extracted three times with DCM, the organic fractions collected, washed with brine, dried over magnesium sulfate and evaporated to give a brownish/yellow oil. The crude mixture was applied to a column of silica gel and eluted with a 2:1 hexane-ethyl acetate solution (Rf=0.16) to give 132 mg of product (54% yield) as a yellow oil. MS: (ESI-TOF) MH+ expected: 306.1812, found: 306.1807.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])C.O.[OH-].[Li+]>C1COCC1.O>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:13])[C:6]=1[CH2:5][C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)Cc1c(C)cccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.3 %

Procedure:
To a mixture of (2,6-dimethyl-phenyl)-acetic acid ethyl ester (13.3 g, 69.2 mmol) in THF (550 mL) and water (224 mL) was added lithium hydroxide monohydrate (23.2 g, 553 mmol). The resulting mixture was stirred vigorously at rt. After 72 h, the mixture was heated to 50° C. for an additional 24 h. The mixture was cooled to rt and concentrated. To the resulting residue was added aqueous 2 N HCl (300 mL) to afford a colorless precipitate. The precipitate was collected by vacuum filtration and further purified by FCC to provide a colorless solid (8.9 g, 78%). MS (ESI): mass calcd. for C10H12O2, 164.1; m/z found, 163.1 [M−H]+. 1H NMR (CDCl3): 7.17-6.90 (m, 3H), 3.72 (s, 2H), 2.33 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23](=O)[CH2:24][CH3:25])[CH2:17][CH2:16]1.Cl.O>O1CCOCC1>[CH2:24]([C:23]1([CH2:22][CH2:21][N:18]2[CH2:17][CH2:16][N:15]([CH3:14])[CH2:20][CH2:19]2)[C:6]2[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH2:11][CH2:12][O:13]1)[CH3:25]
Reactant: CCC(=O)CCN1CCN(C)CC1
Reactant: COc1ccc(CCO)cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCC1(CCN2CCN(C)CC2)OCCc2cc(OC)c(OC)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A mixture of 34,8 g of 3,4-dimethoxybenzeneethanol and 32 g of crude 1-(4-methylpiperazinyl)pentane-3-one in 400 ml of dioxane, which is saturated with anhydrous hydrochloric acid, was stirred at ambient temperature for 24 h. After addition of water the mixture was extracted with dichloromethane. The organic phase was washed, dried and evaporated to yield 41,5 g (68,5%) of crude 1-[2-(1-ethyl-3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)ethyl]-4-methylpiperazine.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[F:18]C1(CC(C2C=CC=CC=2)=O)C=CN=CC1>>[F:18][C:12]1([C:3](=[N:2][OH:1])[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])[CH:13]=[CH:14][N:15]=[CH:16][CH2:17]1
Reactant: O=C(C(=NO)c1ccncc1)c1ccccc1
Reactant: O=C(CC1(F)C=CN=CC1)c1ccccc1
Product: O=C(C(=NO)C1(F)C=CN=CC1)c1ccccc1

Procedure:
The title compound was prepared using the same procedure (U.S. Pat. No. 3,940,486) employed to prepare 2-hydroxyimino-2-(4-pyridyl)acetophenone, except using 4-fluoro-2-(4-pyridyl)-acetophenone.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]([F:16])([F:15])[F:14])(=O)=O)=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=1[OH:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=1[O:26][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: OCc1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccc(Cl)c(OCC(F)(F)F)c1
Temperature: 100 °C
Yield: 71.1 %

Procedure:
A mixture of 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (1.34 g, 5.28 mmol), 2-chloro-5-(hydroxymethyl)phenol (837 mg, 5.28 mmol), K2CO3 (1.46 g, 10.56 mmol) and DMF (9 mL) was heated to 100° C. overnight. It was then poured into ice-water and extracted with ethyl acetate twice. Organic phase washed with water twice, brine and dried with Na2SO4, concentrated to a residue which was purified by flash column chromatograph to give the title compound (903 mg, 75%). 1H NMR (400 MHz, CDCl3): δ 1.77 (1H, t, J=5.6 Hz), 4.42 (2H, q, J=8.0 Hz), 4.68 (2H, d, J=5.2 Hz), 6.99 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.02 (1H, s), 7.37 (1H, d, J=8.0 Hz).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].[CH3:18][NH2:19]>CN(C=O)C>[F:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8]([NH:19][CH3:18])=[O:9]
Reactant: CN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (15 g, 130 mmol) was added slowly to a solution of acid 2-fluoro-4-nitro-benzoic acid (20 g, 110 mmol) in DMF (20 mL) at −5° C. The mixture was stirred for an additional 1 h at −5° C. At 0° C., a methylamine solution (2M, 400 mL, 800 mmol) in tetrahydrafuran was added drop-wise to the solution. The reaction mixture was slowly warmed to 25° C. and then poured into ice-water (125 mL). The suspension was extracted with ethyl acetate (2×200 mL). Combined organic phase was washed with brine (1×200 mL), dried (MgSO4) and concentrated to dryness in vacuo. The title compound 21 was obtained as a yellow solid (20 g, 90% yield). MS: 163 (M+H)+. 1H NMR (acetone-d6, 500 MHz): δ 7.66 (1H, dd, J=8.5, 8.5 Hz), 6.41 (1H, dd, J=8.6, 2.1 Hz), 6.32 (1H, dd, J=13.6, 2.0 Hz), 3.05 (3H, d, J=4.4 Hz).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[C:17]([CH:29]3[CH2:31][CH2:30]3)[C:18]3[O:25][C:22]4([CH2:24][CH2:23]4)[CH2:21][C:20]([CH3:27])([CH3:26])[C:19]=3[CH:28]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+]>CO>[CH:29]1([C:17]2[C:18]3[O:25][C:22]4([CH2:24][CH2:23]4)[CH2:21][C:20]([CH3:26])([CH3:27])[C:19]=3[CH:28]=[C:15]([C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:32])=[O:2])=[CH:12][CH:11]=3)[CH:16]=2)[CH2:30][CH2:31]1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(C#Cc3ccc(C(C)(C)C(=O)O)cc3)cc21
Temperature: 55 °C

Procedure:
A solution of 2-{4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-phenyl}-2-methyl-propionic acid methyl ester (Intermediate 2, 0.046 g, 0.107 mmol) in methanol (5 mL) was treated with a 1M solution of sodium hydroxide (1.2 mL, 1.2 mmol) and the resulting reaction mixture was heated at 55° C. for 4 h. The reaction mixture was cooled to ambient temperature and the volatiles were evaporated in vacuo to a residue that was neutralized with 10% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid after flash column chromatography over silica gel (230-400 mesh) (0.067 g, 89%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([N:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][CH:10]=[CH2:11])=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>CCO>[CH2:12]([N:8]([CH2:9][CH:10]=[CH2:11])[C:7]1[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH:13]=[CH2:14]
Reactant: C=CCN(CC=C)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: C=CCN(CC=C)c1ccc(N)cc1
Yield: 73.9 %

Procedure:
A mixture of 4-nitro-N,N-di(prop-2-en-1-yl)aniline (12.22 g, 55.98 mmol) and tin (II) chloride dihydrate (64.45 g, 279.9 mmol) in EtOH (280 ml) was stirred and heated under reflux for 21 h. The cooled reaction mixture was concentrated under reduced pressure to a volume of 100 ml, and neutralised by the addition of 5 M NaOH. The precipitate was removed by filtration and the filtrate was extracted with EtOAc (4×200 ml). The combined organics were washed with brine (2×200 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a brown oil that was purified by chromatography (1:1 Hexane/EtOAc) to give the title compound (7.79 g, 74%) as a brown oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[C:17]([NH:21][OH:22])([CH3:20])([CH3:19])[CH3:18]>C(Cl)(Cl)Cl>[C:17]([N+:21]([O-:22])=[CH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=CCCc1ccccc1
Reactant: CC(C)(C)NO
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[N+]([O-])=CCCc1ccccc1
Reaction time: 22 h
Yield: 45.1 %

Procedure:
To a mixture of 3-phenylpropionaldehyde (10.0 g, 74.5 mmol, 1.0 equiv) and benzene (150 ml) was added chloroform (25 ml) until a clear solution was obtained. To the clear solution was added N-tert-butylhydroxylamine (7.31 g, 82.0 mmol, 1.1 (equiv) and the resulting mixture was refluxed under nitrogen and Dean-Stark trap for 22 h. Upon cooling oil separated. Oil was separated and product purified by flash chromatography (hexanes: EtOAc=1:1) to give N-tert-butyl-C-(2-phenylethyl)nitrone (7.31 g, 45.1%) as a light color oil: 1H NMR (CD3OD) δ 7.30–7.27 (m, 2H, Ar—H), 7.23–7.19 (m, 3H, Ar—H), 6.80 (t, 1H, Ar—H), 2.77–2.62 (m, 4H, 2CH2), 1.46 (s, 9H, t-Bu).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[C:13]([Cl:19])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.Cl[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28]>C1COCC1.C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[C:13]([Cl:19])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(CO)c(Cl)c2)n1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)[Si](OCc1ccc(-n2nc(C(C)(C)C)cc2N)cc1Cl)(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
To a solution of 3-(tert-butyl)-1-(3-chloro-4-(hydroxymethyl)phenyl)-1H-pyrazol-5-amine (1.15 g, 70% purity, 2.9 mmol) in dry THF (10 mL) under N2 was added imidazole (320 mg, 4.7 mmol) and chlorotriisopropylsilane (970 μL, 870 mg 4.5 mmol) and the reaction mixture maintained at RT for 18 hr. The resulting mixture was diluted with DCM (5.0 mL) and was treated with an additional aliquot of chlorotriisopropylsilane (970 μL, 870 mg, 4.5 mmol) and after a further 5 hr with imidazole (320 mg, 4.7 mmol). After 20 hr the reaction mixture was treated for a third time with chlorotriisopropylsilane (200 μL, 180 mg, 0.90 mmol) and imidazole (100 mg, 1.6 mmol) and after 3 days was evaporated in vacuo. The residue was taken up into EtOAc (20 mL) and was washed with water (20 mL) and brine (10 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 0-100%, gradient elution) and then by SCX capture and release to afford a blue oily liquid which comprised of a mixture of starting material and the desired product. This mixture was taken up into THF (1.0 mL) and was treated with imidazole (50 mg, 0.74 mmol) chlorotriisopropylsilane (140 μL, 130 mg, 0.65 mmol) and maintained at RT for 24 hr and then evaporated in vacuo. The residue was taken up EtOAc (10 mL) and was washed with water (10 mL) and brine (10 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 0-100%, gradient elution) to afford the title compound, Intermediate A22 as a white solid (300 mg, 24%); Rt 3.42 min (Method 2); m/z 436 (M+H)+, (ES+).