Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH:23]4[CH2:27][CH2:26][O:25][CH2:24]4)=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][N+:10]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>O1CCCC1.CO.C(OCC)(=O)C.[Zn]>[NH2:10][CH2:9][CH:8]([C:7]1[C:2]([CH3:1])=[C:3]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:4]=[CH:5][CH:6]=1)[C:13]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH:23]3[CH2:27][CH2:26][O:25][CH2:24]3)=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(OC3CCOC3)ccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(OC3CCOC3)ccc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.9 %

Procedure:
A mixture of benzyl 2-methyl-3-(2-nitro-1-(6-(tetrahydrofuran-3-yloxy)-1H-indol-3-yl)ethyl)phenylcarbamate (0.720 g, 1.397 mmol), ammonium chloride (1.121 g, 20.95 mmol), and zinc dust (1.370 g, 20.95 mmol) in tetrahydrofuran (35 mL) and methanol (35 mL) was stirred at room temperature for 4.5 hr. The mixture was diluted with ethyl acetate (40 mL) and filtered through CELITE®. The filtrate was concentrated under vacuum, and the residue was diluted with water (40 mL), basified with saturated NaHCO3 solution, and extracted with ethyl acetate (4×40 mL). The combined extract was washed with brine (40 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (0.678 g, 1.396 mmol, 100% yield) as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[S:16][CH:17]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:18]([O:20][C@H:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:39])[F:40])=[C:33]([O:41][CH2:42][CH:43]3[CH2:44][CH2:45]3)[CH:32]=2)[CH2:28][C:27]2[C:26]([Cl:46])=[CH:25][N+:24]([O-:47])=[CH:23][C:22]=2[Cl:21])=[O:19])[S:16][CH:17]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N(c1csc(C(=O)O)c1)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(c1csc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a solution of 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-thiophene-2-carboxylic acid (Int. 44) (100 mg, 0.311 mmol) in DCM (5 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (131 mg, 0.311 mmol), EDC (179 mg, 0.934 mmol) and DMAP (19.01 mg, 0.156 mmol) were added, and reaction was stirred at RT overnight. The mixture was diluted with DCM (10 ml) and washed with 1N HCl; the aqueous phase was extracted with EtOAc and the combined organic layers were dried over sodium sulfate. The solvent was removed under vacuum and the crude was purified by flash chromatography on silica gel (DCM/MeOH=98/2) affording (S)-4-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)thiophene-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (Int. 45) (72 mg, 0.100 mmol, MS/ESI+722.9 [MH]+).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:13]Br>C(O)(=O)C>[Br:13][C:4]1[C:3]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([CH3:1])[NH:6][N:5]=1
Reactant: Cc1[nH]ncc1-c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1[nH]nc(Br)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of 5-methyl-4-phenyl-1H-pyrazole (3.0 g, 18.96 mmol) in acetic acid (glacial, 100 mL) was added bromine (1.457 mL, 28.4 mmol) at room temperature. The reaction was stirred at room temperature for 2 h. After quenched with aqueous solution of Na2SO3 (10% wt aq., 10 mL), the reaction was concentrated and extracted with EtOAc, washed with brine, dried over MgSO4, and purified by silica gel column chromatography to give the title compound as yellow oil (2.8 g). LCMS m/z=236.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3H), 7.24-7.54 (m, 5H), 13.13 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]=[O:26])=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1.Cl.CNC.C(=O)([O-])[O-].[Ca+2].[C:37]([O:41]O)([CH3:40])([CH3:39])[CH3:38].CCCCCCCCCC>C(#N)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([C:25]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:26])=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(C=O)n3c2c1OC[C@@H]3c1ccccn1
Reactant: CC(C)(C)OO
Agent: [Cu+2]
Agent: CNC
Agent: Cl
Solvent: CCCCCCCCCC
Solvent: CC#N
Solvent: O
Product: Cc1noc(C)c1-c1ccc2nc(C(=O)OC(C)(C)C)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 40 °C
Reaction time: 10 h

Procedure:
(4S)-7-(3,5-Dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine-2-carbaldehyde (15 mg, 0.042 mmol) and dimethylamine hydrochloride (0.0041 g, 0.050 mmol) [Aldrich, cat. #126365] were dissolved in acetonitrile (1.5 mL) at room temperature. To the resulting mixture, copper(II) sulfate pentahydrate (0.0005 g, 0.002 mmol) [Aldrich, cat. #209198], calcium carbonate (0.0046 g, 0.046 mmol) [Aldrich, cat. #C6763] and 6.0 M tert-butyl hydroperoxide in decane (0.0076 mL, 0.046 mmol) [Aldrich, cat. #416665] were added. The reaction vessel was capped, degassed, and allowed to stir at 40° C. for 10 hours. After filtration through Celite, the solution was concentrated and the resulting residue was purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) afforded the following three compounds:
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:7]([NH2:9])=[S:8].Cl.[CH2:11](O)C>[OH-].[Na+].CI>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[N:6]=[C:7]([S:8][CH3:11])[NH2:9]
Reactant: NC(=S)Nc1nncs1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CSC(N)=Nc1nncs1
Temperature: 40 °C

Procedure:
A mixture of 4.8 g of 1,3,4-thiadiazol-2-ylthiourea (from Example 1B) in 45 ml of lN sodium hydroxide, 15 ml of ethanol and 4 ml of methyl iodide was heated at 40° C for ten minutes. The mixture was acidified by adding 50 ml of lN hydrochloric acid. The reaction mixture was concentrated by evaporation under reduced pressure. The precipitated solid was collected by filtration and dried to give 3.02 g of N'-1,3,4-thiadiazol-2-ylcarbamimidothioic acid, methyl ester. m.p. 116-117° C.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[C:14]([N+:25]([O-:27])=[O:26])=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17]>CN(C)C=O>[CH:5]1([CH2:4][O:12][C:13]2[C:14]([N+:25]([O-:27])=[O:26])=[C:15]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(OCC2CC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
(Bromomethyl)cyclopropane (136 g, 1.01 mol) and potassium carbonate (173 g, 1.25 mol) were added to a solution of methyl 3-hydroxy-4-methoxy-2-nitrobenzoate (190 g, 837 mmol) and dimethylformamide (1 L). The mixture was stirred at room temperature overnight and then quenched with water/ice (3 L). The resulting solids were collected by filtration, washed with water (500 mL×3), and then dried in an oven to give 220 g of methyl 3-(cyclopropylmethoxy)-4-methoxy-2-nitrobenzoate as a yellow solid. MS (ESI): 281.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[S:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27]>>[CH:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([S:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:36])[CH:30]=1)([CH3:28])[CH3:27]
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)C)on4)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Using the procedure described in Example 113C 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (107 mg, 0.3 mmol) was reacted with phenyl 5-isopropylisoxazol-3-ylcarbamate described in Example 133A (110 mg, 0.45 mmol). The mixture was stirred at 50° C. overnight. Upon cooling to room temperature, the product precipitated out of the solution. The solid was filtered off and washed with diethyl ether to give 1-(5-isopropylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea (72.22 mg, 47%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.02 (s, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.53-7.28 (m, 5H), 6.51 (s, 1H), 4.34 (bs, 2H), 4.00 (s, 3H), 3.76 (bs, 2H), 3.34 (s, 3H), 3.04-3.00 (m, 1H), 1.23 (s, 6H); LC-MS (ESI) m/z 510 (M+H)+.
Reaction SMILES: C([O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]=[CH2:15])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])C=C.[OH-].[Na+].Cl>C(O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:19])=[O:4])=[C:7]([N+:16]([O-:18])=[O:17])[CH:8]=1)[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)c1ccc(OCC=C)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 89.6 %

Procedure:
4-allyloxy-2-nitro-benzoic acid allyl ester [J. Org. Chem. 1987, 52(18), 4086] (0.21 g, 0.8 mmol) was dissolved in ethanol (5 ml), and 40% sodium hydroxide added (5 ml). The mixture was stirred for 16 h then acidified to pH 2 with 2M hydrochloric acid. The mixture was extracted with ethyl acetate (3×25 ml) and the combined organic phases washed with brine (75 ml), dried (MgSO4) and concentrated to yield 4-allyloxy-2-nitrobenzoic acid as brown solid (0.16 g);
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[C:8]([CH3:27])=[C:9]2[C:14](=[C:15]([F:18])[C:16]=1F)[N:13]([C@@H:19]1[CH2:21][C@@H:20]1[F:22])[CH:12]=[C:11]([C:23]([OH:25])=[O:24])[C:10]2=[O:26].Cl.Cl.[N:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[NH:33][CH2:32][CH2:31]2>C(N(CC)CC)C>[N:30]12[CH2:37][CH:34]([CH2:35][CH2:36]1)[N:33]([C:16]1[C:15]([F:18])=[C:14]3[C:9]([C:10](=[O:26])[C:11]([C:23]([OH:25])=[O:24])=[CH:12][N:13]3[C@@H:19]3[CH2:21][C@@H:20]3[F:22])=[C:8]([CH3:27])[C:7]=1[F:6])[CH2:32][CH2:31]2
Reactant: C1CN2CCC(C2)N1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(F)c(N2CCN3CCC2C3)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To 5 ml of dried N,N-dimethylformamide were added 211 mg of 6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 372 mg of 1,4-diazabicyclo[3.2.1]octane dihydrochloride, and 2 ml of triethylamine, and the mixture was stirred at 100° C. for 1 hour. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a 1N sodium hydroxide aqueous solution while cooling with ice. After neutralizing with 1N hydrochloric acid, the mixture was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting crude crystals were recrystallized from a mixed solvent of ethanol and 28% aqueous ammonia. The precipitated crystals were collected by filtration, washed with diethyl ether, and dried at 60° C. in vacuo overnight to yield 170 mg of the titled compound as a yellow powder.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][C@H:27]([OH:29])[C@@H:26]([OH:30])[C@H:25]([OH:31])[C@H:24]1[CH2:32][OH:33]>CN(C=O)C>[S:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH:27]([OH:29])[CH:26]([OH:30])[C@H:25]([OH:31])[CH:24]2[CH2:32][OH:33])=[O:11])[S:2]1
Reactant: OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1CCCCl
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCC[C@@H]1CCSS1)OCCCN1CC(O)C(O)[C@H](O)C1CO
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-[(3R)-1,2-dithiolan-3-yl]pentanoic acid 6 (500 mg, 2.42 mmol) in DMF (5 mL) was added K2CO3 (1.4 g, 9.69 mmol) at room temperature and the mixture was stirred for 30 min. Then a solution of hydrochloride salt of (2R,3R,4R,5S)-1-(3-chloropropyl)-2-(hydroxymethyl)piperidine-3,4,5-triol 5 (581 mg, 2.1 mmol) in DMF (5 mL) was added to the reaction mixture and the mixture was heated at 60° C. for 16 h. The reaction mixture was then filtered through a celite pad, washed with DCM (100 mL). The filtrate was concentrate under reduced pressure to get crude which was purified by column chromatography using 100-200 mesh silica gel and eluting with 6% methanol in DCM to afford 3-[(3R)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidin-1-yl]propyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate, compound 7 (300 mg, 30%) as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][C:10]1=[O:19].[OH-:20].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:17]1[CH:16]=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH2:11][C:10]([OH:19])=[O:20]
Reactant: [OH-]
Reactant: O=C1Cc2cc(O)ccc2N1c1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1cc(O)ccc1Nc1c(Cl)cccc1Cl
Yield: 95 %

Procedure:
A solution of 1-(2,6-dichlorophenyl)-5-hydroxy-2-indolinone (2.0 g, 6.8 mmol) in 25 mL of 2.5N NaOH is heated at reflux for 2 hours. The cool reaction mixture is diluted with 20 mL of water and washed with ethyl ether. The basic layer is acidified with concentrated HCl and extracted with ethyl acetate (2×25 mL). The organic phase is washed with brine and dried (Na2SO4). Removal of solvent affords the product (2.0 g, 95%) as a brown foam (of suitable purity for use in the next step).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:7]=O)[CH3:2].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][C:30]#[N:31])=[CH:28][C:23]=2[O:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27](/[C:29](=[CH:7]/[C:6]3[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)/[C:30]#[N:31])=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: CCOc1cc(C=O)ccc1OCCCCCCO
Reactant: N#CCc1ccc2c(c1)OCO2
Product: CCOc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCO
Yield: 96 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{3-ethoxy-4-[(6-hydroxyhexyl)oxy]phenyl}prop-2-enenitrile is prepared starting from 3-ethoxy-4-[(6-hydroxyhexyl)oxy]benzaldehyde and 1,3-benzodioxol-5-ylacetonitrile according the same procedure following for example 10 in 96% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)[N:4]=1.[CH:22]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][S:27]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)(=[O:29])=[O:28])=[CH:14][CH:13]=2)[N:4]=1
Reactant: O=S(=O)(Cl)C1CCCC1
Reactant: NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: O=S(=O)(NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)C1CCCC1

Procedure:
The title compound was prepared from ({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine and cyclopentanesulphonyl chloride using a similar procedure to that described for Example 88.
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[C:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])[CH3:13]>CO>[O:11]=[C:6]([CH2:13][C:12](=[O:14])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(=O)c1cccnc1
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.7 %

Procedure:
Sodium methoxide (5.4 g, 100 mmol) and dimethyloxalate (11.8 g, 100 mmol) were dissolved in anhydrous methanol (700 mL) and stirred at room temperature under nitrogen until a suspension was formed. To this mixture, 3-acetylpyridine (5.5 mL, 50 mmol) was added and the stirring was continued for 3 days at room temperature. The reaction was quenched with enough 5% aqueous KHSO4 until all solids have dissolved. The methanol was removed under reduced pressure, and the residue was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (2×200 mL), brine and dried (NaSO4) followed by the removal of solvent under reduced pressure to give the title compound (8.67 g, 84% yield) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 9.21-9.20 (m, 1H), 8.84-8.82 (m, 1H), 8.30-8.26 (m, 1H), 7.50-7.45 (m, 1H), 7.08 (s, 1H), 3.96 (s, 3H). 13C NMR (CDCl3, 75 MHz) δ 188.5, 170.4, 162.2, 153.9, 149.0, 135.2, 130.5, 123.8, 98.0, 53.3. mass spectrum (APIMS) m/z 208 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([CH:13]=O)[N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.Cl.NO.[N:41]1C=CC=CC=1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[CH:12]=[C:11]([C:13]#[N:41])[N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1cc(COc2cc(C#N)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Yield: 86 %

Procedure:
A mixture of 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carbaldehyde (990 mg), hydroxylamine hydrochloride (200 mg), pyridine (1 mL) and ethanol (10 mL) was refluxed for 3 hrs. After concentration of the reaction mixture, dilute hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in acetic anhydride (20 mL), and the mixture was refluxed for 5 hrs. After concentration of the reaction mixture, The residue was subjected to silica gel column chromatography to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-phenyl-1H-pyrazole-5-carbonitrile (850 mg, yield 86%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, v/v). The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 120-121° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1([CH3:10])[O:9][CH2:8][CH2:7][O:6]1.II.[Mg].[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2([C:26]#[N:27])[CH2:25][CH2:24][CH2:23]2)[CH:18]=[CH:19][C:20]=1[Cl:21].[BH4-].[Na+]>O1CCCC1.CC(O)C>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]2([CH:26]([NH2:27])[CH2:2][CH2:3][CH2:4][C:5]3([CH3:10])[O:9][CH2:8][CH2:7][O:6]3)[CH2:25][CH2:24][CH2:23]2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: CC1(CCCBr)OCCO1
Agent: II
Agent: [BH4-]
Agent: [Mg]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC1(CCCC(N)C2(c3ccc(Cl)c(Cl)c3)CCC2)OCCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A portion (10 ml) of a solution of 2-(3-bromopropyl)-2-methyl-1,3-dioxolane (27.5 g) in dry tetrahydrofuran (70 ml) and an iodine crystal were added to a mixture of magnesium (3.5 g) and tetrahydrofuran (10 ml). The mixture was heated under reflux and a further portion (10 ml) added. When the reaction had been initiated the remaining solution was added over 40 minutes and reflux was maintained. 1-(3,4-Dichlorophenyl)cyclobutanecarbonitrile (18 g) and then dry tetrahydrofuran (10 ml) were added and the resulting solution heated under reflux for two hours. The solution was cooled, a slurry of sodium borohydride (5 g) and propan-2-ol (50 ml) was added and the mixture stirred at ambient temperature for 16 hours. Propan-2-ol (100 ml) was added and the mixture heated under reflux for 2.75 hours and then cooled and poured into ice/water (1000 g). The aqueous mixture was extracted with ether and the extract was dried and evaporated to give 1 -[1-(3,4-dichlorophenyl)cyclobutyl]-4-(2-methyl-1,3-dioxolan-2-yl)butylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][CH2:8][N:9]2[CH2:16][CH:15]3[C:17](=O)[CH:11]([CH2:12][Se:13][CH2:14]3)[CH2:10]2)=[CH:5][CH:4]=1.NN.[OH-].[K+].C([O-])([O-])=O.[K+].[K+].Cl(O)(=O)(=O)=O>C(O)COCCOCCO.CCOCC.C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:10][CH:11]3[CH2:17][CH:15]([CH2:14][Se:13][CH2:12]3)[CH2:16]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CCN2CC3C[Se]CC(C2)C3=O)cc1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: OCCOCCOCCO
Solvent: CCOCC
Product: COc1ccc(CCN2CC3C[Se]CC(C3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
A jacketed flask equipped for simple distillation was charged with a suspension of 7-p-methoxyphenethyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (0.65 g, 1.92 mmol), hydrazine (95%, 1.00 g, 29.7 mmol), and potassium hydroxide (85%, 3.0 g, 45.5 mmol) in triethylene glycol (25 mL). Under a rapid stream of nitrogen, the suspension was heated to 140°-145° C. by boiling xylene in the jacket of the flask. Stirring was continued at this temperature for 3 hours during which time a small amount of water and excess hydrazine distilled from the reaction mixture. After cooling to room temperature, the resulting solution was diluted with water (100 mL) and was extracted with ether (5×40 mL). The combined ether were dried (K2CO3) overnight and 60% perchloric acid (0.5 g, 3.0 mmol) was added very slowly. This precipitated an orange solid. The ether was decanted and the solid was recrystallized (absolute ethanol) with the aid of decolorizing carbon to give 0.58 g (71%) of 7-p-methoxyphenethyl-3-selena-7-azabicyclo[3.3.1]nonane hydroperchlorate as white needles: mp 208.5°-209.0° C.; IR (KBr) cm-1 3425, 1085; 1H NMR (DMSO-d6) δ1.73 [br d, 1H, H(9), J=14 Hz], 1.90 [br d, 1H, H(9), J=14 Hz], 2.42 [br s, 2H, H(1,5)], 2.65 [d, 2H, H(2,4)ax, J=12 Hz], 3.02 [t, 2H, H(11-ArCH2) J=7 Hz], 3.22 [d, 2H, H(2,4), J=14 Hz], 3.30 [m, 2H, H(10-NCH2)], 3.36 [d, 2H, H(6,8)ax, J=12 Hz], 3.76 [s, 3H, OCH3 ], 3.86 [d, 2H, H(6,8)eq, J=12 Hz], 6.97 [d, 2H, H(3',5'), J=9 Hz], 7.32 [d, 2H, H(2',6'), J=9 Hz], 8.92 [br s, 1H, H(7)]; 13C NMR (DMSO-d6) ppm 21.9 [t, C(2,4)], 25.3 [d, C(1,5)], 28.5 [t, C(9) or C(11)], 28.9 [t, C(11-ArCH2) or C(9)], 55.0 [q, OCH3 ], 56.7 [t, C(6,8)], 58.9 [t, C(10-NCH2)], 114.0 [d, C(3',5')], 127.7 [s, C(1')], 129.6 [d, C(2',6')], 158.1 [s, C(4')]; 15N NMR (DMSO-d6) ppm 48.10 [N(7)]; 77Se NMR (DMSO-d6) ppm 88.64 [Se(3)]. Analysis calculated for C16H24ClNO5Se: C, 45.24; H, 5.69; N, 3.30; Se, 18.59. Found: C. 45.42; H, 5,80; N, 3.30; Se, 18.46. ##STR27##