Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH3:8])[N:3]=1.CC(C)([O-])C.[K+].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.CCCCCC>C1COCC1.C(OCC)(=O)C>[F:15][C:16]1[CH:17]=[C:18](/[CH:19]=[CH:1]/[C:2]2[CH:7]=[N:6][CH:5]=[C:4]([CH3:8])[N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Cc1cncc(C)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cncc(/C=C/c2cccc(F)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
2,6-Dimethylpyrazine (5.0 g, 46 mmol) was dissolved in THF (200 mL) and cooled to 0° C. Potassium t-butoxide (46 mL of a 1.0M solution in THf, 46 mmol) was added to afford a dark red solution. The solution was allowed to warm to ambient temperature and stir for 1 hr. The solution was then cooled to 0° C., and 3-fluorobenzaldehyde (4.9 mL, 46 mmol) was added via syringe pump over 2 h. The reaction was then allowed to slowly warm to ambient temperature. After stirring at ambient temperature for 18 h, the reaction mixture was cooled to 0° C. and quenched by the addition of concentrated aqueous HCl (10 mL). The resulting suspension was allowed to warm to ambient temperature for 15 minutes, then cooled to 0° C. and brought to pH=8 by addition of solid NaHCO3. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3.times.200 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography eluting with 90:10, 85:15, then 80:20 hexane:ethyl acetate to afford 2-[(E)-2-(3-fluorophenyl)ethenyl]-6-methylpyrazine (4.14 g, 42% yield) as a light yellow solid. M.p. 43-44° C. 1H NMR (CDCl3, 300 MHz) Δ8.44 (s, 1H), 8.31 (s, 1H), 7.29 (d, J=16 Hz, 1H), 7.37-7.26 (m, 3H), 7.12 (d, J=16 Hz, 1H), 7.05-6.98 (m, 1H), 2.59 MS (ESI) 214.5 (M+). This material was carried on to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])[C:25]([Cl:39])=[CH:24][N:23]=1>>[Cl:39][C:25]1[C:26]([NH:28][C@@H:29]2[C@@H:34]3[CH2:35][C@@H:31]([CH:32]=[CH:33]3)[C@@H:30]2[C:36]([NH2:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@H:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: COc1c(Nc2ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n2)ccc2c1CC[C@@H](N1CCOCC1)CC2

Procedure:
The title compound was prepared from 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (1S,2S,3R,4R)-3-(2,5-dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 881 heating at 140° C. Product was isolated as an off-white solid (43 mg, 39%). LCMS (m/e) 539 (M+H); 1H NMR (CDCl3, 400 MHz) δ 8.16 (d, 1H, J=8.1 Hz), 7.86 (s, 1H), 7.41 (broad s, 1H), 6.88 (d, 1H, J=8.3 Hz), 6.31 (s, 2H), 5.81 (s, 1H), 5.62 (s, 1H), 4.27 (t, 1H, J=8.1 Hz), 3.97 (s, 4H), 3.72 (s, 3H), 3.39-3.54 (m, 2H), 3.08 (m, 4H), 2.88 (m, 2H), 2.75 (dd, 1H, J=11.9, 14.2 Hz), 2.49 (d, 1H, J=8.1 Hz), 2.42 (m, 3H), 2.20 (d, 1H, J=9.4 Hz), 1.61 (d, 1H, J=8.3 Hz), 1.50 (m, 2H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C(N(CC)CC)C.[F:12][C:13]1[C:18]([C:19](Cl)=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([F:24])[C:14]=1[F:25].CC[O:28]CC>>[F:12][C:13]1[C:18]([C:19]([OH:28])=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([F:24])[C:14]=1[F:25].[F:12][C:13]1[C:18]([C:19]([OH:28])=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([F:24])[C:14]=1[F:25].[CH2:1]([NH2:4])[CH2:2][NH2:3]
Reactant: CCOCC
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: NCCN
Product: O=C(O)c1c(F)c(F)c(F)c(F)c1F

Procedure:
Ethylene diamine (130 mg, 2.1 mmol) and triethylamine (510 mg, 5.0 mmol), together dissolved in 10 mL anhydrous ether is added to pentafluorobenzoyl chloride (1.2 g, 5.0 mmol) in 10 mL anhydrous ether. White precipitate is obtained and filtered off. The residue is washed with chloroform, then water and then filtered to recover ethylene diamine bis(pentafluorobenzoate) (III) as white needle crystals (yield, 100%). Sodium azide (270 mg, 4.2 mmol) in 1.7 mL water and 4.0 mL DMF is then reacted with III (870 mg, 2.0 mmol) in 20 mL DMF, and stirred overnight on a 60° C. hotplate. A white precipitate is obtained. The solution is reduced to half-volume by evaporation and the precipitate is filtered off (yield, 35%), dried and recrystallised from DMF to give ethylene diamine bis(4-azido-2,3,5,6-tetrafluorobenzoate) (IV) as white crystals. FTIR: 2129 (N3 asymmetric stretch), 1666 (C═O stretch), 1554, 1483, 1242 (N3 symmetric stretch), no acid OH band at 3000-3500.
Reaction SMILES: Cl.[CH:2]1([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCOCC1>[C:24]1([CH2:23][O:22][C:20]([N:11]2[CH2:10][CH2:9][C:8]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]2)=[O:21])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)C1(C2CCCCC2)CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(C2CCCCC2)CC1
Temperature: 5 °C
Yield: 74286.4 %

Procedure:
A 2-L, three-necked, round-bottomed flask equipped with a mechanical stirrer and two addition funnels was charged with 4-cyclohexyl-4-piperidinecarboxylic acid hydrochloride (8-3) (157.9 g, 0.637 mol), 1 L of dioxane, and 255 mL of 5 N NaOH solution. The mixture was cooled at about 5° C., and then benzyl chloroformate (92 mL, 0.643 mmol) and 127 mL of 5 N NaOH solution were added dropwise simultaneously via two separate addition funnels while maintaining the temperature at or below 10° C. The reaction was monitored by TLC and, upon completion, the resulting mixture was diluted with 1 L of water and concentrated. The residue was diluted with 2 L of water and the pH was adjusted to about 12 using 5 N NaOH solution. The mixture was then extracted with 1 L of ethyl acetate. The aqueous layer was acidified to pH 1.5-2.0 using 2 N HCl solution, and extracted with three 1-L portions of ethyl acetate. The combined organic layers were washed with 1 L of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to give 165 g of title compound 8-4 as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]1[C:37](=[O:38])[N:36]([CH3:39])[C@@H:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:34](=[O:44])[NH:33][C@@H:32]([C@H:45]([OH:47])[CH3:46])[C:31](=[O:48])[N:30]([CH3:49])[CH2:29][C:28](=[O:50])[N:27]([CH3:51])[C@@H:26]([CH2:52][CH:53]([CH3:55])[CH3:54])[C:25](=[O:56])[NH:24][C@@H:23]([CH2:57][O:58][C:59]([CH3:62])([CH3:61])[CH3:60])[C:22](=[O:63])[N:21]([CH3:64])[C@@H:20]([C@H:65]([CH2:67][CH3:68])[CH3:66])[C:19](=[O:69])[NH:18][C@H:17]([C:70]([N:72]2[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]2)=[O:71])[CH2:16]S[CH2:14][C:13](=[O:78])[N:12]([CH3:79])[C@@H:11]([CH3:80])[C:10](=[O:81])[N:9]1[CH3:82])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[O:85][S:86]([O-:88])=O.[K+].CS(C)=O>CO>[CH2:1]([CH:8]1[C:37](=[O:38])[N:36]([CH3:39])[CH:35]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:34](=[O:44])[NH:33][CH:32]([C@H:45]([OH:47])[CH3:46])[C:31](=[O:48])[N:30]([CH3:49])[CH2:29][C:28](=[O:50])[N:27]([CH3:51])[CH:26]([CH2:52][CH:53]([CH3:54])[CH3:55])[C:25](=[O:56])[NH:24][CH:23]([CH2:57][O:58][C:59]([CH3:60])([CH3:62])[CH3:61])[C:22](=[O:63])[N:21]([CH3:64])[CH:20]([C@H:65]([CH2:67][CH3:68])[CH3:66])[C:19](=[O:69])[NH:18][CH:17]([C:70]([N:72]2[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]2)=[O:71])[CH2:16][S:86](=[O:88])(=[O:85])[CH2:14][C:13](=[O:78])[N:12]([CH3:79])[CH:11]([CH3:80])[C:10](=[O:81])[N:9]1[CH3:82])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@H]1C(=O)N[C@H](C(=O)N2CCCCC2)CSCC(=O)N(C)[C@@H](C)C(=O)N(C)[C@@H](Cc2ccccc2)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](COC(C)(C)C)C(=O)N1C
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: CC[C@H](C)C1C(=O)NC(C(=O)N2CCCCC2)CS(=O)(=O)CC(=O)N(C)C(C)C(=O)N(C)C(Cc2ccccc2)C(=O)N(C)C(CC(C)C)C(=O)NC([C@@H](C)O)C(=O)N(C)CC(=O)N(C)C(CC(C)C)C(=O)NC(COC(C)(C)C)C(=O)N1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.2 %

Procedure:
(5S,8S,11S,14S,20S,23S,26S,29R)-8-Benzyl-23-(tert-butoxymethyl)-26-((S)-sec-butyl)-14-((R)-1-hydroxyethyl)-11,20-diisobutyl-4,5,7,10,16,19,25-heptamethyl-29-(piperidine-1-carbonyl)-1-thia-4,7,10,13,16,19,22,25,28-nonaazacyclotriacontane-3,6,9,12,15,18,21,24,27-nonone (9.6 mg, 8.19×10−3 mmol) was dissolved in methanol (0.6 ml), and water (0.3 ml) was added. While stirring the solution, oxone (15.1 mg, 2.46×10−2 mmol) was added. The reaction mixture was stirred at room temperature for 14 hours, and DMSO (80 μl) was then added. The mixture was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=60/40→0/100) to afford 5S,8S,11S,14S,20S,23S,26S,29R)-8-benzyl-23-(tert-butoxymethyl)-26-((S)-sec-butyl)-14-((R)-1-hydroxyethyl)-11,20-diisobutyl-4,5,7,10,16,19,25-heptamethyl-29-(piperidine-1-carbonyl)-1-thia-4,7,10,13,16,19,22,25,28-nonaazacyclotriacontane-3,6,9,12,15,18,21,24,27-nonaone 1,1-dioxide (8.3 mg, 84%).
Reaction SMILES: [CH:1]([C:4]1[S:22][C:7]2[NH:8][C:9](=[O:21])[N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11](=[O:12])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+]>C(#N)C>[CH:1]([C:4]1[S:22][C:7]2[N:8]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:47])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:9](=[O:21])[N:10]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11](=[O:12])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cc2c(=O)n(CCc3ccccc3)c(=O)[nH]c2s1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CC#N
Product: CC(C)c1cc2c(=O)n(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of 6-isopropyl-3-(2-phenylethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.40 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.68 g), potassium carbonate (0.35 g) and acetonitrile (16 mL) was stirred at room temperature for 2 hr. Insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL) and methanol (4 mL). 1N Aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.46 g, 64%).
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1.[NH3:23].CO.C(Cl)(Cl)[Cl:27]>>[ClH:27].[NH2:23][CH2:22][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1
Reactant: O=c1cc(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Reactant: N
Reactant: ClC(Cl)Cl
Solvent: CO
Product: Cl
Product: NCC(O)COc1ccc2c(=O)cc(-c3ccccc3)oc2c1

Procedure:
7-(2,3-Epoxypropoxy)flavone (13.3 g, 0.045 mol) in a presurre bottle was treated with a methanolic solution (90 ml) containing 1.87 g of ammonia (0.11 mol). The bottle was sealed and the suspension was heated at 50° for 12 hrs. A tlc (15% MeOH/CHCl3) indicated that the starting material was gone, and the reaction mixture was cooled and filtered. The solid (5.32 g) thus obtained was shown by tlc to be a byproduct, m.p. 209°-12°. The filtrate, upon evaporation, afforded 7.0 g of a yellow solid, m.p. 121°-27°, which was purified by high pressure liquid chromatography to give 1.85 g of yellow powder, m.p. 154°-56°. (13% yield). The hydrochloride salt was prepared and recrystallized from MeOH, m.p. 191°-2°.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][CH2:14][O:15][C:16](Cl)=[O:17].[CH3:19][O-:20].[Na+].O>CN1CCCC1=O>[CH3:19][O:20][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:13][CH2:14][O:15][C:16]2=[O:17])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)OCCCl
Reactant: C[O-]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(N2CCOC2=O)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
4-Fluoro-3-nitro-aniline (50.0 g) is dissolved in 100 ml N-methyl-pyrrolidone. Subsequently 2-chloroethyl-chloroformate (48.1 g) is added dropwise under external cooling, whereupon the internal temperature is kept below 60° C. After completion of the addition stirring is continued for 30 minutes and then a 30% methanolic sodium methoxide solution (230.7 g) is added dropwise in such a rate that under external cooling the temperature remains below 40° C. When the addition is completed, the reaction mixture is allowed to cool and then poured into cold water (2000 ml) and stirred for additional 30 minutes. The obtained suspension is filtered off, washed with water, and dried.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].Cl.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)=[O:9]
Reactant: Fc1ccccc1
Reactant: Cc1c(C(=O)Cl)cccc1[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1c(C(=O)c2ccc(F)cc2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 41 h

Procedure:
150 g of aluminum chloride were added over 30 minutes at 40° C under an argon atmosphere to a suspension of 107.8 g of 2-methyl-3-nitro-benzoyl chloride (Step A -- Example IV) in 450 ml of fluorobenzene and the mixture was held at this temperature for 41 hours. After icing, the mixture was added to 1 liter of ice water and 250 ml of concentrated hydrochloric acid and after stirring for 30 minutes, the mixture was extracted with methylene chloride. The extract was washed with water, then with N sodium hydroxide and then with water until the wash water was neutral. The solution was dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure to obtain 115.7 g of 2-methyl-3-nitro-4'-fluorobenzophenone in the form of white crystals. For analysis, a sample of the product was crystallized from n-pentane and had a melting point of 64° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33][C:34]2=O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1COCC1>[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33]/[C:34]/2=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[CH:30][CH:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C[Si](C)(C)C
Reactant: O=C1CCc2ccc(OCc3ccccc3)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)/C=C1\CCc2ccc(OCc3ccccc3)cc21
Temperature: -78 °C
Yield: 38 %

Procedure:
At −78° C., lithium bis(trimethylsilyl)amide (1.0 M in hexanes) (4 mL, 26 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (4 g, 26 mmol) in THF (20 mL). The reaction mixture was maintained at −78° C. for 22 minutes. 1.2 (3.5 g, 15 mmol) in THF (20 mL) was then added slowly to the mixture. The mixture was stirred at −78° C. and allowed to warm to room temperature overnight. The reaction mixture was then poured into water (30 mL) and extracted with EtOAc (300 mL). The organic layers were washed with brine and dried over anhydrous sodium sulfate. After removing solvent by rotary evaporation, the residue was purified by column chromatography (1:4 EtOAc/hexane). The Product 1.3 was obtained in 38% yield as a white solid.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH2:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH:31][C:32](=[O:45])[C:33]1[CH:38]=[C:37]([S:39](=[O:42])(=[O:41])[NH2:40])[CH:36]=[CH:35][C:34]=1[O:43][CH3:44])[CH3:24]>>[CH2:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH:31][C:32](=[O:45])[C:33]1[CH:38]=[C:37]([S:39](=[O:41])(=[O:42])[NH:40][C:4](=[O:21])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[O:11][CH3:12])[CH:36]=[CH:35][C:34]=1[O:43][CH3:44])[CH3:24]
Reactant: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)ccc1OC
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC(=O)C(O)=CC(=O)N(Cc2ccc(F)cc2)OC)ccc1OC

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with N-(1-ethyl-pyrrolidin-2-ylmethyl)-2-methoxy-5-sulfamoyl-benzamide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 1.29 (t, 3, J=7), 1.86 (m, 1), 2.06 (m, 2), 2.26 (m, 1), 2.97 (m, 2), 3.50 (m, 1), 3.59 (s, 3), 3.64 (m, 1), 3.82 (m, 2), 3.95 (m, 1), 4.03 (s, 3), 4.72 (s, 2), 6.37 (s, 1), 6.95 (m, 2), 7.10 (m, 1), 7.23 (m, 2), 8.23 (m, 1), 8.71 (s, 1).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.C(=O)([O-])O.[Na+].Br[CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)C>O>[NH3:5].[CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:25]/[CH:26]=[CH:27]/[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6]2
Reactant: BrC/C=C/c1ccccc1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C/C=C/c3ccccc3)CC21
Product: N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 23.5 %

Procedure:
To a solution of the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6--yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.89 mmol) in N,N-dimethylfornamide (8 ml) was added sodium hydrogen carbonate (3 g, 36 mmol) and 1-[(E)-3-bromo-1-propenyl]benzene (0.13 ml, 0.89 mmol) and the reaction mixture was heated at 50° C. for 20 h. After cooling, diethyl ether (15 ml) and water (15 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×15 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (40 mg, 12%).
Reaction SMILES: [F:1][C:2](Br)([F:14])[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13].[P:16]([O:23]CC)([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>O1CCOCC1>[F:1][C:2]([F:14])([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[C:3]1[C:8]([F:9])=[C:7]([F:10])[C:6]([F:11])=[C:5]([F:12])[C:4]=1[F:13]
Reactant: Fc1c(F)c(F)c(C(F)(F)Br)c(F)c1F
Reactant: CCOP(OCC)OCC
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)C(F)(F)c1c(F)c(F)c(F)c(F)c1F
Yield: 89.6 %

Procedure:
Perfluorobenzyl bromide (2.00 g, 7.66 mmol) and P(OEt)3 (1.66 g, 9.96 mmol) were dissolved in 1,4-dioxane (10 ml) and heated at reflux for 14 hours. Fractional distillation (66-78° C., 60 mm Hg) afforded the product as a colorless oil (2.43 g, 96%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:32])[NH:10][C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([O:24]C(C)(C)C)=[O:23])[CH:17]=3)=[CH:13][C:12]=2[F:31])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:32])[NH:10][C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=3)=[CH:13][C:12]=2[F:31])=[CH:4][C:3]=1[C:33]([F:35])([F:36])[F:34]
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)ccn1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc(C(=O)O)c2)cc1F
Temperature: 50 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
At room temperature, tert-butyl 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)-3-fluorophenoxy)picolinate (1.8 g, 3.43 mmol) was dissolved in dichloromethane (15 mL). Trifluoroacetic acid (15 mL) and triethyl silane (0.2 mL) was added. The resulted mixture was heated to 50° C. and stirred for 16 h. The solvent was removed under reduced pressure. The residue was partitioned in water (50 mL) and ethyl acetate (50 mL), and separated. The organic phase was removed, and the aqueous layer was filtered. The solid was washed with water (20 mL×2) and dried in vacuum to give the title compound (1.48 g, purity 85%, yield 92%) as a grey solid.
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([CH2:21][CH2:22][O:23]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:20][C:7]1=2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:43][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[CH:18][C:19]([CH2:21][CH2:22][OH:23])=[CH:20][C:7]1=2
Reactant: CN(C)CCC=C1c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: CN(C)CCC=C1c2ccccc2COc2ccc(CCO)cc21
Yield: 76.1 %

Procedure:
In this example, 0.92 g of 11-(3-dimethylaminopropylidene)-2-(2-triphenylmethyloxyethyl)-6,11-dihydrodibenz[b,e]oxepin is dissolved in a mixed solvent of 20 ml of water and 20 ml of dioxane. To the solution is added 60 mg of p-toluene sulfonic acid and the mixture is heated at reflux for two hours. The solvent is distilled away under reduced pressure and the residue is extracted with 200 ml of ethylacetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium hydrochloride solution in oder and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure. The resultant residue is purified by column chromatography on silica gel (eluent: ethylacetate triethylamine=10:1 ) to obtain 0.4 g of the desired product.