Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]([NH:6][CH:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][CH:13]=3)[N:9]([CH3:23])[CH2:8]1)=[O:5])[CH3:2].B(F)(F)F.CCOCC.S(Cl)([Cl:38])(=O)=O>C(#N)C.C(Cl)Cl>[Cl:38][C:13]1[NH:14][C:15]2[C:22]3[C:12]=1[CH2:11][C@@H:10]1[C@@H:20]([C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:21][C@@H:7]([NH:6][C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:24][CH3:25])[CH2:8][N:9]1[CH3:23]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCN(CC)C(=O)NC1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC#N
Product: CCN(CC)C(=O)N[C@@H]1C[C@@H]2c3cccc4[nH]c(Cl)c(c34)C[C@H]2N(C)C1

Procedure:
In the same was as described in Example 7, 340 mg of 1,1-diethyl-3(6-methylergolinyl)urea (1 millimole) was dissolved in 19 ml of anhydrous acetonitrile and 0.3 ml of boron trifluoride etherate in 5 ml of anhydrous methylene chloride and reacted with 0.09 ml of freshly distilled sulfuryl chloride, dissolved in 10 ml of anhydrous methylene chloride. The product was worked up and chromatographed as described in Example 7, thus obtaining 270 mg of 3-(2-chloro-6-methyl-8β-ergolinyl)-1,1-diethylurea.
Reaction SMILES: O[C:2]1C=C2C(=CC=1)C(C(O)=O)=CC=C2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27]([OH:29])=[O:28])=[CH:22][CH:21]=[CH:20]2>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27]([O:29][CH3:2])=[O:28])=[CH:22][CH:21]=[CH:20]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: COc1ccc2c(C(=O)O)cccc2c1
Product: COC(=O)c1cccc2cc(OC)ccc12

Procedure:
The process according to claim 1, wherein 6-hydroxy-1-naphthoic acid in the form of a mixture with 6-methoxy-1-naphthoic acid is reacted to give methyl 6-methoxy-1-naphthoate.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC(C)([O-])C.[K+].[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N+]([O-])=O)=[C:18]([CH:21]=1)[C:19]#[N:20]>CN(C=O)C.CCOCC>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])=[C:18]([CH:21]=1)[C:19]#[N:20]
Reactant: CC(C)=NO
Reactant: COc1ccc([N+](=O)[O-])c(C#N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(ON=C(C)C)c(C#N)c1
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
In 400 ml of DMF was dissolved acetone oxime (34.5 g) followed by potassium t-butoxide (51 g). After this mixture had stirred for 30 minutes, 5-methoxy-2-nitro-benzonitrile (70 g) was added. After stirring overnight, the reaction was diluted with ether (~4 L) and filtered. The filtrate was washed with ethyl acetate and combined organics were washed with water (3×1.5 L), dried (MgSO4) and concentrated in vacuo. Preparative liquid chromatography (silica gel) eluting with 4:1 heptane/EtOAc yielded the expected product (10 g).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:87][CH2:86][CH2:85][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([N:59]([CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH:74][C@H:75]([C:81]([O:83]C)=[O:82])[CH2:76][CH2:77][CH2:78][CH2:79][NH2:80])=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])[CH3:60])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].FC(F)(F)C([O-])=O.N>O>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:87][CH2:86][CH2:85][C@H:24]1[C:25]([NH:27][C@H:28]([C:36]([NH:38][C@H:39]([C:46]([NH:48][C@H:49]([C@H:54]([CH2:56][C:57]([N:59]([CH2:61][C:62]([NH:64][C@H:65]([C:72]([NH:74][C@H:75]([C:81]([OH:83])=[O:82])[CH2:76][CH2:77][CH2:78][CH2:79][NH2:80])=[O:73])[CH2:66][C:67]1[N:71]=[CH:70][NH:69][CH:68]=1)=[O:63])[CH3:60])=[O:58])[OH:55])[CH2:50][CH:51]([CH3:53])[CH3:52])=[O:47])[CH2:40][C:41]1[N:45]=[CH:44][NH:43][CH:42]=1)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: COC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CN(C)C(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N
Agent: N
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)[C@@H](O)CC(=O)N(C)CC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCCCN)C(=O)O
Temperature: 25 °C

Procedure:
110 mg of H-Arg-Arg-Pro-Phe-His-Sta-Sar-His-Lys-OMe (in the form of the trifluoroacetate; see Example 18) are dissolved in 1 ml of H2O and the pH value is adjusted to 5.0 with 0.5N NH3. After the addition of 20 μl of a 1% aqueous trypsin solution, the pH value is maintained at 5.0 by means of a pH stat while stirring at room temperature and adding 0.1N NH3. After approximately 10-15 minutes the absorption of the base is complete. The solution is acidified with 200 μl of glacial acetic acid, heated for 2 minutes in a boiling water bath, and lyophilised. In order to be converted into the acetate, the residue is dissolved in H2O and filtered slowly through a column (φ=0.7 cm; length=8 cm) of weakly basic ion exchanger (formexample Merck No. II) equilibrated in 0.05N acetic acid. The eluate is concentrated to a small volume and lyophilised, yielding H-Arg-Arg-Pro-Phe-His-Sta-Sar-His-Lys-OH (in acetate form) as an amorphous, readily water-soluble powder; Rf (D)=0.03; Rf (M)=0.03; Rf (O)=0.03.
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[Cl:18][C:19]1[N:24]=[C:23]([C:25](=O)[CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][CH:20]=1>C(O)C>[Cl:18][C:19]1[N:24]=[C:23]([C:25]2[C:26]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[CH:29][CH:28]=3)=[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]3[N:2]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cc1ccnc2ccccc12)c1cccc(Cl)n1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Temperature: 110 °C
Yield: 18.8 %

Procedure:
Add 1-aminopyridinium iodide (780 mg, 3.53 mmol), N,N-diisopropylethylamine (0.62 mL, 3.53 mmol), 1-(6-chloro-pyridin-2-yl)-2-quinolin-4-yl-ethanone (500 mg, 1.77 mmol), and ethanol (8 mL) to a sealed tube apparatus. The sealed vessel is heated at 110° C. for 5 hours. After cooling, the crude is concentrated in vacuo. Purification by flash column chromatography (Silica Gel, 25-40% acetone/hexanes) provides the title compound 119 mg (19%) as an orange solid.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[C:11]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN1CCOCC1.Cl.[CH3:29][N:30]([CH3:47])[C:31]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:36][CH2:35][C:34](=[CH:37][C:38](O)=[O:39])[CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:47][N:30]([CH3:29])[C:31]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:36][CH2:35][C:34](=[CH:37][C:38]([NH:20][CH2:19][CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:39])[CH2:33][CH2:32]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Reactant: NCCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 72 h
Yield: 55 %

Procedure:
1-Hydroxybenzotriazole (273 mg, 2.0 mmol), 3-phenyl-1-propylamine (0.142 ml, 1.0 mmol) and N-methylmorpholine (0.222 ml, 2.0 mmol) were added to a solution of (4-dimethylamino-4-phenylcyclohexylidene)acetic acid hydrochloride (300 mg, 1.0 mmol) in dry dimethylformamide (10 ml) under argon. The solution was cooled to 0° C. and dicyclohexylcarbodiimide (417 mg, 2.0 mmol) was added. The reaction mixture was stirred at RT for 3 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The filtrate obtained was extracted with ether. 5 M sodium hydroxide solution (2 ml, 10 mmol) was added to the aqueous phase and the mixture was diluted with water (200 ml). The product thereby precipitated out as a colourless solid and was to be obtained in a yield of 55% (209 mg) with an m.p. of 140-142° C.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH2:6][CH2:7][CH2:8][F:9])[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCCC1.O>[C:4]([C:3]([NH:2][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH2:6][CH2:7][CH2:8][F:9])[CH3:10])#[N:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(C#N)CCCF
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C#N)(CCCF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude rac-2-amino-5-fluoro-2-methylpentanonitrile hydrochloride product from Example 76A was initially charged in 185 ml of tetrahydrofuran/water (1:1), and 32.09 g (232.18 mmol) of potassium carbonate and 10.63 g (62.29 mmol) of benzyl chloroformate were added. The reaction mixture (biphasic mixture) was stirred at room temperature overnight. Another 1.93 g (11.33 mmol) of benzyl chloroformate were added to the reaction and the mixture was stirred at room temperature for a further 2 h. Subsequently, the biphasic system was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, and then dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient=20/1 to 5/1). 11.77 g of the target compound were obtained (72% of theory over two stages, 92% purity).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)([CH3:12])[CH2:9]2)C=CC=CC=1.[ClH:25]>C(O)C.[OH-].[OH-].[Pd+2]>[ClH:25].[ClH:25].[CH3:12][C:10]1([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:9][NH:8][CH2:11]1
Reactant: CC1(N2CCOCC2)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CC1(N2CCOCC2)CNC1
Yield: 74.9 %

Procedure:
A mixture of 4-[1-(diphenylmethyl)-3-methyl-3-azetidinyl]morpholine (1.05 g, 3.26 mmol), 10% Pd(OH)2 (0.12 g) in ethanol (30 ml) and 1N HCl (7 ml) was treated with H2 at 60 psi overnight. The catalyst was removed by filtration, and the solvent was evaporated under vacuum. The residue was washed with benzene (3×5 ml) and dried under high vacuum to provide 4-(3-methyl-3-azetidinyl)morpholine dihydrochloride (0.52 g, 74.9%). LCMS: (M+H)+ 156.9.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10]([OH:12])=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.S(=O)(=O)=O.N1C=CC=CC=1>C(Cl)Cl.CS(C)=O>[O:12]=[C:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C=C(O)C1
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-boc-3-(hydroxyl)azetine (1.0 g, 5.8 mmol) and triethylamine (1.6 mL, 12 mmol) in CH2Cl2 (10 mL) and DMSO (4 mL) at 0° C. was added pyridine sulfur trioxide (1.8 g, 12 mmol). The reaction was allowed to warm to room temperature. After 18 h, the reaction mixture was partitioned between CH2Cl2 (100 mL) and 1M aqueous citric acid solution (100 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to afford tert-butyl 3-oxoazetidine-1-carboxylate as a crude oil. 1H NMR (600 MHz, DMSO-D6) 4.67 (s, 4H); 1.47 (s, 9H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH:8]([CH2:16][N:17]1[CH2:33][CH2:32][C:20]3([N:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][NH:22][C:21]3=[O:31])[CH2:19][CH2:18]1)[CH2:7]2.[BH4-].[Na+]>CO.O>[OH:15][C@@H:9]1[C:10]2[C:6](=[CH:5][C:4]([O:3][CH3:2])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH2:7][C@H:8]1[CH2:16][N:17]1[CH2:18][CH2:19][C:20]2([N:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][NH:22][C:21]2=[O:31])[CH2:32][CH2:33]1
Reactant: COc1cc2c(cc1OC)C(=O)C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OC)[C@@H](O)[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
8-[(2,3-Dihydro-5,6-dimethoxy-1-oxo-1H-inden-2-yl)methyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, hydrochloride (1:1) (20.0 g finely ground) is slurried in methanol (400 ml), cooled in ice, and treated dropwise with an excess of sodium borohydride dissolved in water (75 ml). The resulting mixture is stirred for 16 hours at room temperature. Dilution with water (400 ml), extraction with methylene chloride, and concentration of the dried methylene chloride extracts in vacuo yield the crude product. Crystallization of this material from absolute ethanol yields 13.3 g of isomerically pure title compound, melting point 189°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:35]=[CH:34][C:16]([C:17]([N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[S:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:26]1[C:24]2[CH2:25][N:19]([C:17]([C:16]3[CH:15]=[CH:14][C:13]([NH:12][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=4[Cl:1])=[CH:35][CH:34]=3)=[O:18])[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[S:22][C:23]=2[CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Sc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
To a solution of 452 mg of 2,4-dichlorobenzoyl chloride in 6 ml of methylene chloride is added 0.6 g of 10-(4-aminobenzoyl)-10,11-dihydrodibenz[b,f][1,4]thiazepine followed by 0.375 ml of triethylamine. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is washed with 20 ml of water, 1N HCl, 1N Na2CO3, water and dried over MgSO4. The filtrate is evaporated in vacuo to give 0.72 g of yellowish solid which is purified by silica gel chromatography on thick layer plates by elution with 1:1 ethyl acetate-hexane to give 0.254 g of the desired product as ivory crystals, m.p. 112°-115° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([O:27]C3CCCCO3)[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[CH:14][CH:13]=2)=[C:6]([CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2].Cl>CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]([OH:27])[C:19]3[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=3)[C:22]#[N:23])=[CH:16][CH:17]=2)=[C:6]([CH3:34])[C:5]=1[OH:35])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(NCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)c(C)c1O
Agent: Cl
Solvent: CO
Product: CC(=O)c1ccc(NCc2ccc(C(O)c3cccc(C#N)c3)cc2)c(C)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.7 %

Procedure:
To 3-[{4-[(4-acetyl-3-hydroxy-2-methyl-phenylamino)-methyl]-phenyl}-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (538 mg, 1.1 mmol) in MeOH (5 mL) is added conc. HCl (0.33 mL). The reaction mixture is stirred at RT for 6 h. The reaction mixture is concentrated and the residue partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer is separated and the aqueous extracted with EtOAc (2×). The organic layers are combined, washed with brine, dried over Na2SO4, and concentrated. The residue is purified by flash column chromatography using 40% EtOAc/hexane as eluent. Obtained is the title compound as yellow foam (305 mg, 72%). LC-MS (m/e): 385 (M−1).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:14])=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:15]([O-])([O-])=O.[Cs+].[Cs+].IC.O>CO>[CH3:15][O:6][C:5](=[O:7])[C:4]1[C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=[C:2]([F:1])[C:3]=1[CH3:14]
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CO
Product: COC(=O)c1c([N+](=O)[O-])ccc(F)c1C
Temperature: 25 °C

Procedure:
To a solution of 3-fluoro-2-methyl-6-nitro-benzoic acid in 200 mL of methanol, Cs2CO3 (4.34 g, 13.3 mmol) is added and stirred at the room temperature. The solution is concentrated under reduced pressure then the resulting yellow solids are suspended in 26 ml of DMF. Iodomethane (1.7 ml 26.6 mol) is added at 0° C. and stirred at the room temperature for 30 min. Water is added to the solution and extracted with ethyl acetate. The organic layer is washed with H2O followed by brine, dried over Na2SO4, filtered and evaporated in vacuo to afford 3-fluoro-2-methyl-6-nitro-benzoic acid methyl ester (5.70 g) as yellow oil in quantitative yield. 1H-NMR (400 MHz, δ, ppm) CDCl3: 2.30 (d, 3H), 3.99 (s, 3H), 7.22 (dd, 1H), 8.07 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:15]([Br:16])=[CH:14][C:5]2[C:6]([C:10]([NH:12][CH3:13])=[O:11])=[C:7]([I:9])[O:8][C:4]=2[CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].O.O[Li].O>N1C=CC=CC=1>[Br:16][C:15]1[C:2]([NH:1][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:3][C:4]2[O:8][C:7]([I:9])=[C:6]([C:10]([NH:12][CH3:13])=[O:11])[C:5]=2[CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1c(I)oc2cc(N)c(Br)cc12
Agent: [Li]O
Solvent: O
Solvent: c1ccncc1
Product: CNC(=O)c1c(I)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
To a solution of 6-amino-5-bromo-2-iodo-N-methylbenzofuran-3-carboxamide (1 g, 2.53 mmol) in pyridine, MsCl (580 mg, 5.06 mmol) was added dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred for 1.5 h. After the solvent was removed in vacuo, the reaction mixture was adjusted to pH=5-6 with 1 N HCl aq. After filtration, the solid was dissolved in THF:H2O=5:1 (15 mL) and then LiOH.H2O (800 mg, 20 mmol) was added. The mixture was stirred for 30 minutes at room temperature. After the solvent was removed in vacuo, the reaction mixture was adjusted to pH=5-6 with 1 N HCl aq. Finally the precipitate was collected to give 5-bromo-2-iodo-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (800 mg, 90% purity by HPLC, yield: 60%), which was used for the next step without further purification. 1H-NMR (CDCl3, 400 MHz) δ 8.37 (s, 1H), 7.84 (s, 1H), 6.86 (s, 1H), 6.29 (s, 1H), 3.07 (d, J=4.8 Hz, 3H), 2.99 (s, 3H). MS (M+H)+: 473/475.
Reaction SMILES: [CH2:1]=[C:2]([C:7](OS(F)(=O)=O)([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].[I-:15].[Na+].COCCOCCOC>O>[F:4][C:3]([F:6])([F:5])[C:2]([C:7]([F:9])([F:8])[I:15])=[CH2:1]
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: C=C(C(F)(F)F)C(F)(F)I
Reaction time: 8 h
Yield: 55.2 %

Procedure:
CH2═C(CF3)CF2OSO2F (10 g, 0.04 mole) is added gradually to a mixture of dry sodium iodide (Nal) (7 g, 0.047 mole) and dry diglyme (20 ml) at 10° C. with stirring. The reaction mixture is kept overnight and then poured into water. The organic layer is separated, washed with aqueous sodium bicarbonate solution and then with water and then dried over MgSO4. Distillation gives a mixture (6 g, 54%) of 2-trifluoromethyl-3,3,-difluoro-3-iodopropene (CH2═C(CF3)CF2I) (10%) and 1,1-difluoro-2-trifluoromethyl-3-iodopropene (CF2═C(CF3)CH2I) (90%), as shown by GC-MS and 19F NMR. B.pt. 98-99° C. The difluoromethylene isomer CF2═C(CF3)CH2I predominates in this example. The experience with chloride as nucleophile (Example 17), indicates that reaction conditions, time in the case of Example 17, can be varied to control the ratio of methylene to difluoromethylene isomer. Simple experimentation should identify conditions at which iodide as nucleophile will yield higher amounts of methylene monomer.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH3:35][O:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([NH:43][NH2:44])=[O:42])=[CH:39][CH:38]=1.CCN(CC)CC>CN(C=O)C.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:44][NH:43][C:41](=[O:42])[C:40]2[CH:45]=[CH:46][C:37]([O:36][CH3:35])=[CH:38][CH:39]=2)=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(C(=O)NN)cc1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)NNC(=O)c2ccc(N)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-amino-3-nitrobenzoic acid (3.64 g, 20 mmol) in DMF (50 mL) was added HOBT (2.70 g, 20 mmol) and EDCI (3.83 g, 20 mmol). After the addition, the solution was stirred at 25° C. for 10 min then 4-methoxybenzoic acid hydrazide (3.32 g, 20 mmol) was added and followed by the addition of NEt3 (8.35 mL, 60 mmol). The solution was stirred at 25° C. overnight and water was added. The resulting suspension was filtered and the solid was washed with water. The yellow solid was dried under reduced pressure and was purified by flash chromatography (heptane/EtOAc=1:3) to give the title compound. MS: m/z 331 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:28]([O:29][CH3:30])=[CH:27][C:12]([C:13]([N:15]2[CH:19]=[C:18](CC(OC)=O)[CH2:17][C@H:16]2[CH2:25]O)=[O:14])=[C:11]([N+:31]([O-])=O)[CH:10]=1)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:30][O:29][C:28]1[C:9]([O:8][CH3:1])=[CH:10][C:11]2[N:31]=[CH:25][C@@H:16]3[CH2:17][CH2:18][CH2:19][N:15]3[C:13](=[O:14])[C:12]=2[CH:27]=1
Reactant: COC(=O)CC1=CN(C(=O)c2cc(OC)c(OCc3ccccc3)cc2[N+](=O)[O-])[C@H](CO)C1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC)C(=O)N1CCC[C@H]1C=N2

Procedure:
Finely ground Cd/Pb couple (3.12 g) was added portion wise to a solution of 105 (1 g, 2.2 mmol) THF (10 mL) and NH4OAc (1M, 10 mL). The reaction was followed by TLC (EtOAc), when no starting material was present, the mixture was poured into ethyl acetate (400 mL). The organic phase was dried over MgSO4 and evaporated to yield the crude product, which was purified by flash chromatography (EtOAc) to give of the pure compound as a pale yellow oil (0.45 g, 78%): 1H NMR (270 MHz, CDCl3) δ2.08 (m, 2H); 2.29 (m, 2H); 3.53-3.63 (m, 1H); 3.72 (m, 1H); 3.79-3.85 (m, 1H); 3.93 (s, 3H); 3.96 (s, 3H); 6.82 (s, 1H); 7.52 (s, 1H); 7.68 (d, J=4.4, 1H). 13C NMR (67.8 MHz, CDCl3) δ24.2; 29.6; 46.7; 53.7; 56.0; 56.1; 109.4; 111.2; 140.7; 147.5; 151.3; 162.5; 164.6. IR (Nujol): cm−1 3000-2800, 1601, 1450, 1434, 1500, 1453, 1263, 1217, 1010, 908, 735. MS: m/e (relative intensity) 260 (M+, 100), 245 (50), 231 (25), 217 (10), 191 (20), 164 (25), 136 (20), 121 (5), 93 (8), 70 (10). HRMS Calculated for C14H16N2O3: 260.1160. Found: 260.1161. [α]25D=+1004.7° (c=0.17, CHCl3).