Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH:12]2[CH2:15][O:14][CH2:13]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:16][C:17]([CH3:26])([CH3:25])[CH:18]([NH2:24])[C:19]1[S:20][CH:21]=[CH:22][N:23]=1>>[CH3:16][C:17]([CH3:26])([CH3:25])[CH:18]([NH:24][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH:12]2[CH2:15][O:14][CH2:13]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:19]1[S:20][CH:21]=[CH:22][N:23]=1
Reactant: O=C(O)c1cc(OC2COC2)c(Cl)cn1
Reactant: CC(C)(C)C(N)c1nccs1
Product: CC(C)(C)C(NC(=O)c1cc(OC2COC2)c(Cl)cn1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Chloro-4-(oxetan-3-yloxy)-pyridine-2-carboxylic acid (Example 23a) and 2,2-Dimethyl-1-thiazol-2-yl-propylamine (CAN 1247122-26-4) as starting materials and isolated (21.6 mg, 37%) as white solid; MS (ESI, m/z): 382.3 (M+H+).
Reaction SMILES: CS(O[CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(=O)=O.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C)C=O>[N:31]([CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)N=[N+]=[N-]

Procedure:
A solution of 1.35 g. of ethyl 15-methanesulfonyloxy 9-oxo-prostanoate (Example 90) in 60 ml. of N,N-dimethylformamide containing 1.25 g. of sodium azide is heated on the steam-bath for 18 hours. The cooled solution is poured into 300 ml. of water and the resulting mixture is extracted several times with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. The residual oil is chromatographed on silica gel to give 737 mg. (62%) of oil; λmax. 4.77 (azido) and 5.78 μ (carbonyl groups).
Reaction SMILES: FC1C=CC(C(=O)CBr)=CC=1.[C:12]([CH:14]([CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].FC1C=CC(C2NC=C(C(OCC)=O)C=2)=CC=1.[H-].[Na+].[C:49]1([S:55](Cl)(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C)C=O.O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[N:13]([S:55]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)(=[O:57])=[O:56])[CH:12]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCOC(=O)c1c[nH]c(-c2ccc(F)cc2)c1
Agent: O=C(CBr)c1ccc(F)cc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2ccccc2)c1
Reaction time: 0.25 h
Yield: 68 %

Procedure:
Using 4-fluorophenacyl bromide instead of phenacyl bromide, a procedure as in Reference Example 1 was performed to synthesize ethyl 2-cyano-4-(4-fluorophenyl)-4-oxobutanoate, and procedures as in Reference Examples 2 and 3 were performed to synthesize ethyl 5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate. Sodium hydride (60% in oil, 0.32 g) was added to a solution (20 mL) of ethyl 5-(4-fluorophenyl)-1H-pyrrole-3-carboxylate (1.56 g) in N,N-dimethylformamide under ice-cooling. The mixture was stirred at the same temperature for 15 min, added benzenesulfonyl chloride (1.41 g), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→7:2) to give the title compound as crystals (yield 1.70 g, 68%).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C@@H:10]([C:12](O)=[O:13])[NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].II>C1COCC1>[NH2:11][C@@H:10]([CH2:9][O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:12][OH:13]
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N[C@H](CO)COCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
A mixture of O-(phenylmethyl)-L-serine (commercial product) (139.0 g; 0.712 mol) and NaBH4 (96%; 75 g; 1.9 mol) in dry THF (700 mL, distilled on sodium/benzophenone), under N2 atmosphere, was slowly added (1.5 hours) with a solution of I2 (181.0 g; 0.713 mol) in dry THF (350 mL) at a temperature of 0 to 15° C. When the addition was completed and the dark color had disappeared, the mixture was refluxed for 18 hours, then cooled at 0° C. and the NaBH4 excess was destroyed with cold water (30 mL), followed by 15N KOH (320 mL). When bubble evolution was no longer observed, the mixture was heated, distilling most of the organic solvent (THF). The aqueous mixture was refluxed for 6 hours, then stirred at r.t. for a further 18 hours. CHCl3 (700 mL) and Et2O (300 mL) were added thereto under strong stirring; after 15 minutes the diphasic mixture was filtered through Celite® and the separated solid was repeatedly washed with CHCl3/Et2O 3:1 (4 L). The filtered solution was concentrated, removing water by repeated azeotropical distillations with CH3CN. The crude oil (130 g) was purified twice by flash chromatography (CH2Cl2/CH3OH/NH4OH 25% (w/w) 54:40:6 to 90:9:1), thereby obtaining the desired compound (92.63 g; 0.511 mol). Yield: 72%.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)[CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[OH-].[K+]>CO>[CH3:32][O:31][C:29]1[CH:30]=[C:25]([C:21]2[CH:20]=[C:19]([CH2:18][O:17][CH:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)[CH:24]=[CH:23][N:22]=2)[CH:26]=[C:27]([O:35][CH3:36])[C:28]=1[O:33][CH3:34]
Reactant: COc1cc(-c2cc(COC3CCN(C(=O)OCc4ccccc4)CC3)ccn2)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2cc(COC3CCNCC3)ccn2)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(benzyloxycarbonyl)-4-[[2-(3,4,5-trimethoxyphenyl) pyridin-4-yl]methyloxy]piperidine (213 mg) in methanol (10 mL) was added 40% aqueous potassium hydroxide (10 mL). The mixture was stirred at 100° C. for 3 hours and evaporated. Water was added to the residue and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residual oil was subjected to column chromatography of silica gel using chloroform-ammonia saturated methanol (20:1) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc(N)c2ncccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: COc1cc(NS(=O)(=O)c2ccccc2)c2ncccc2c1
Yield: 63.6 %

Procedure:
In the similar fashion using route 14 general procedure 27, 6-methoxyquinolin-8-amine (Intermediate 23) (250 mg, 1.43 mmol), benzenesulfonyl chloride (220 μl, 1.3 mmol) and DMAP (cat.) gave the title compound (260 mg, 57%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.C([Li])CCC.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[N:27]2[CH2:30][C:29](=O)[CH2:28]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O>C1COCC1.CN(C)C1C=CN=CC=1.CCOCC>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:26]([C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=2)[N:27]2[CH2:30][C:29](=[C:4]([C:5]3[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=3)[C:3]([O:2][CH3:1])=[O:13])[CH2:28]2)=[CH:33][CH:34]=1
Reactant: COC(=O)Cc1cc(F)cc(F)c1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COC(=O)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.83 g (20.57 mmol) of methyl(3,5-difluorophenyl)acetate in 30 mL of THF was added a solution of 8.6 mL (21.51 mmol) of butyllithium (2.5M solution in hexanes) and stirred for 30 minutes at −78° C. A solution of 5.73 g (18.7 mmol) of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 10 mL THF was added and the solution was stirred for 2 h at −78° C. Then 2.28 g (18.6 mmol) of 4-dimethylaminopyridine, 3.3 mL(l 8.7 mmol) of DIEA and 3.0 mL (37.4 mmol) of methanesulfonyl chloride was added and the solution was stirred for 1 h as it warmed from −78° C. to rt. The reaction mixture was then warmed to 45° C. and stirred for additional 2.5 h. The mixture was poured into 250 mL of ether and washed with 50 mL of aq NaHCO3. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate=15:1 to afford the title compound; 1H-NMR (CDCl3) δ 3.67 (s, 3H), 3.84 (m, 2H), 4.25 (m, 2H), 4.54 (s, 1H), 6.76 (m, 1H), 6.78 (m, 2H), 7.33 (m, 3H), 7.38 (m, 2H); Mass Spectrum: m/e=474 (M+1 35Cl, 35Cl) and 476 (M+1 35Cl, 37Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([CH3:17])[CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC(NCc2ccc(Cl)cc2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(Cc1ccc(Cl)cc1)C1CCC(=O)CC1
Reaction time: 8 h

Procedure:
8.4 g (35 mMol) of 4-[N-(4-chloro-benzyl)-amino]-cyclohexanone are dissolved in 50 ml of absolute dimethylformamide and, after the addition of 2.6 g (18.7 mMol) of potassium carbonate, 5.0 g (35 mMol) of methyliodide are added dropwise at 25°-30° C. After standing overnight the mixture is concentrated, mixed with water and extracted with chloroform. The extracts are dried and concentrated.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N+:30]([O-])([O-:32])=[O:31].[K+].C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:30]([O-:32])=[O:31]
Reactant: COc1cccc2c1CCCC(=O)N2
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CC#N
Product: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55.7 %

Procedure:
To a solution of 6-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (6.8 g, 35.6 mmol) in acetonitrile (50 ml) at −10° C. was added trifluoromethanesulfonic anhydride (15.0 mL, 106.8 mmol) dropwise. After stirring for 20 minutes, potassium nitrate (3.94 g, 39.0 mmol) was added in portions, and the mixture was slowly warmed to room temperature and stirred for another 5 hours, poured into saturated sodium bicarbonate in ice water (100 mL) and adjusted the pH to 9. The aqueous phase was extracted with ethyl acetate and the organic extracts were combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica column chromatography (petroleum ether/ethyl acetate 10/1 to 1/2) to afford the product 6-methoxy-7-nitro-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one as a yellow solid (4.68 g, yield 55.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.01 (s, 1H), 7.80-7.83 (d, 1H, J=8.8 Hz), 6.88-6.90 (d, 1H, J=8.8 Hz), 3.85 (s, 3H), 2.73-2.77 (t, 2H, J=7.2 Hz), 2.25-2.27 (t, 2H, J=6.8 Hz), 2.15-2.20 (m, 2H).
Reaction SMILES: O1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.[S:11]1C2CCCC(=O)C=2C=C1>>[S:11]1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCCc2sccc21
Reactant: NC1CCCc2occc21
Product: NC1CCCc2sccc21

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 6,7-dihydro-1-benzothiophen-4(5H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.09, 7.02, 3.95, 2.79, 2.03, 1.85, 1.62; 13C NMR (100 MHz, CDCl3) δ 140.51, 137.18, 126.77, 122.66, 47.96, 34.24, 25.48, 21.48;
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:9][CH:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[CH:18][CH:17]=2)[O:7]1)=[O:5])[CH3:2].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(O)C.[C].[Pd]>[CH2:14]([O:13][C:11]([C@H:10]1[C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][CH:8]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[O:9]1)=[O:12])[CH3:15]
Reactant: CCOC(=O)[C@@H]1OC(c2ccc(OCc3ccccc3)cc2)O[C@H]1C(=O)OCC
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1OC(c2ccc(O)cc2)O[C@H]1C(=O)OCC
Yield: 97.7 %

Procedure:
A solution of 7.4 g (4R,5R)-2-(4-benzyloxyphenyl)-1,3-dioxolane-4,5-dicarboxylic acid diethyl ester and 0.8 ml of triethylamine in 120 ml of toluene and 40 ml of ethanol was hydrogenated overnight with 1.1 g of 5% palladium carbon at room temperature and normal pressure. After filtration and evaporation of solvent, 5.60 g of (4R,5R)-2-(4-hydroxyphenyl)-1,3-dioxolane-4,5-dicarboxylic acid diethyl ester was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=[CH:6]N(C)C)[CH3:2].Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH2:31])=[NH:30])=[CH:24][CH:23]=1.CCN(CC)CC>CCO.O>[CH2:1]([O:3][C:4]([C:5]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[N:30][C:29]([CH2:28][C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)=[N:31][CH:6]=1)=[O:19])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(C)cc1
Reactant: N=C(N)Cc1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(Cc2ccc(F)cc2)nc1-c1ccc(C)cc1
Yield: 74.3 %

Procedure:
To solution of 3-dimethylamino-2-(4-methyl-benzoyl)-acrylic acid ethyl ester (Tetrahedron, 2002, 58, 8581-8589; 0.567 g, 2.15 mmol) in EtOH (10 mL) was added 2-(4-fluoro-phenyl)-acetamidine hydrochloride (0.405 g, 2.15 mmol) and Et3N (0.90 mL, 6.5 mmol). The mixture was heated at reflux for 18 h, and then was diluted with water and extracted with EtOAc (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (5-20% EtOAc/hexanes) to give 0.560 g (74%) of the title compound. MS (ESI): exact mass calcd. for C21H19FN2O2, 350.14; m/z found, 351.4 [M+H]+. H NMR (CDCl3): 8.97 (s, 1H), 7.51 (d, J=8.2, 2H), 7.38-7.35 (m, 2H), 7.27-7.26 (m, 2H), 7.01-6.97 (m, 2H), 4.32 (s, 2H), 4.23 (q, J=7.1, 2H), 2.42 (s, 3H), 1.16 (t, J=7.1, 3H).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:50])[CH2:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:50])[CH2:42][C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:29][CH2:30][O:31][CH3:32])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
To solid 14 (7.00 g, 9.72 mmol) in a 250 mL round-bottom flask was added TFA (20 mL). The addition was a little bit exothermic. The mixture was stirred at r.t. for 2 h then concentrated and co-evaporated with MTBE (2×100 mL) to obtain a solid that was triturated with MTBE (80 mL) for 2 h. The solid was collected by filtration, washed with MTBE (2×10 mL) and dried in vacuum for 1 h. The dry solid was partitioned between the mixture of DCM/MeOH: (9/1, 300 mL) and NaHCO3 (200 mL). The phases were separated. The organic phase was collected and the aqueous phase was extracted with DCM/MeOH: 9/1 (2×150 mL). Organic phases were combined, washed with brine (100 mL), dried over Na2SO4 and concentrated. The solid residue was triturated with EA (40 mL) for 1 h, collected by filtration, washed with EA (2×5 mL), dried in vacuum for 1 h to afford 15 as beige solid (3.77 g, 63% yield). MS (m/z): 620.6 (M+1).
Reaction SMILES: [CH:1]1([Sn:7]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14](O)[CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.CS(Cl)(=O)=O.[N-:40]=[N+:41]=[N-:42].[Na+]>O.CN(C)C=O>[CH:1]1([Sn:7]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([N:40]=[N+:41]=[N-:42])[CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1ccccc1[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CC(N=[N+]=[N-])c1ccccc1[Sn](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 27.4 %

Procedure:
997 mg of tricyclohexyl [o-(1-hydroxyethyl)phenyl]tin (2.04 mmol) and 20 ml of pyridine were mixed together in a 20 ml two-neck flask, then 269 mg of methane sulfonyl chloride (2.35 mmol) was added dropwise thereto. After the mixture was stirred for 22 hours at a room temperature, a brown-colored solid, which had been obtained by concentrating the reaction solution under reduced pressure, was dissolved in 10 ml of dimethylformamide. Subsequently, 10 ml of a dimethylformamide solution containing 354 mg of sodium azide (5.44 mmol) was added dropwise, and the mixture was then refluxed for 3 hours. After the mixture was cooled to 0° C., and 20 ml of water was added, the organic substance was extracted with 30 ml of ether three times. After the ether layer was washed with 30 ml of a saturated brine, and dried over sodium sulfate, the solvent was removed under reduced pressure to yield a crude product. The resultant crude product was purified by column chromatography on silica gel (for which, 50 g of silica gel, and hexane, as a devleoping solvent were employed) to yield 288 mg of the final product (0.559 mmol).
Reaction SMILES: [C:1](=[N:10][OH:11])([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)([OH:11])(=[O:20])=[O:19].[C:1](=[N:10][OH:11])([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCC(=NO)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the oxime 2 of Example 2 (5.0 g, 33 mmol) dissolved in pyridine (31 mL) was added p-toluenesulfonyl chloride (7.4 g, 39 mmol) and the reaction mixture stirred at room temperature for 24 hours. Pyridine hydrochloride was removed by filtration and the filtrate concentrated under reduced pressure. The solid obtained was slurried in hexanes, filtered, and air dried to give the compound 3 as a pale peach-colored solid: NMR (CDCl3) δ 1.12 (t, 3H, J=8 Hz), 2.45 (s, 3H), 2.81 (q, 2H, J=8 Hz), and 7.27-7.98 (m, 8H).
Reaction SMILES: C(O)[C@@H]([C@@H](CO)O)O.[CH3:9][N:10]1[C@@H:15]2[C@@H:16]3[O:18][C@@H:17]3[C@H:11]1[CH2:12][CH:13]([O:19][C:20]([C@@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][OH:24])=[O:21])[CH2:14]2>>[CH3:9][N:10]1[C@@H:15]2[C@@H:16]3[O:18][C@H:17]3[C@H:11]1[CH2:12][C@@H:13]([O:19][C:20]([C@@H:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:23][OH:24])=[O:21])[CH2:14]2
Reactant: CN1[C@@H]2CC(OC(=O)[C@H](CO)c3ccccc3)C[C@H]1[C@@H]1O[C@@H]12
Agent: OC[C@@H](O)[C@@H](O)CO
Product: CN1[C@@H]2C[C@@H](OC(=O)[C@H](CO)c3ccccc3)C[C@H]1[C@@H]1O[C@H]12

Procedure:
A casting solution was prepared containing 4.0% CMC and 1.0% erythritol. A 10.0 mg aliquot of scopolamine HCl was dissolved into 50 g of the casting solution thereby yielding a scopolamine HCl concentration of 200 μg/g of the casting solution. A 1.2543 g amount of the casting solution containing the drug was equally divided between the three wells of the sample BP strip. PAM® was employed as a release agent. After 45 minutes in the IR drying tunnel the recovered weight was 105% of the theoretical NVS. The resulting films easily released from the casting well and were clear and flexible. Each film swatch averaged 22 mg and contained 8.4 μg of scopolamine HCl.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([O:12][CH3:13])[C:3]=1[O:14][CH2:15][CH:16]([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:42])[NH:37][CH2:36]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:10][CH:9]([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[C:38](=[O:42])[NH:37][CH2:36]3)=[C:3]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:4]=1[O:12][CH3:13]
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: COc1c(OC(F)F)ccc(Br)c1OCC(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)CNC3=O)c1OCC(C)C
Temperature: 85 °C

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (100 mg, 0.371 mmol) in acetonitrile (10 mL), was added potassium carbonate (153.8 mg, 1.114 mmol) and isobutyl bromide (152.6 mg, 1.114 mmol) and the resultant reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 300 mg of 1-Bromo-4-(difluoromethoxy)-2-isobutoxy-3-methoxybenzene as a solid. To a stirring solution of 1-bromo-4-(difluoromethoxy)-2-isobutoxy-3-methoxybenzene (200 mg, 0.615 mmol) in dimethylformamide (5 mL) was purged with argon for 1 h. To this cesium carbonate (599 mg, 1.84 mmol), tetrakis(triphenylphosphine) palladium(0) (35 mg, 0.030 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (191 mg, 0.738 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a (30 mg, 13%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.C(#N)C>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Yield: 90.9 %

Procedure:
A mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (1 g, 4.782 mmol), morpholine (0.46 ml, 5.260 mmol), diisopropylethylamine (1.25 ml, 7.173 mmol) and acetonitrile (10 ml) was refluxed for 8 hours. Water was added to the residue obtained by evaporation of the solvent under reduced pressure. The precipitated crystal was collected by filtration to give the title compound (1.2 g, 91%) as a yellow crystal.