Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:19]([O:18][C:16]([N:13]1[CH2:12][CH2:11][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:2]#[N:1])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(N)=O)cc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 4.5 g of 4-(4-aminocarbonylphenyl)-1-tert.butyloxycarbonyl-piperidine, 6.8 g of triphenylphosphine, 2.4 g of carbon tetrachloride and 1.6 g of triethylamine in 50 ml of chloroform is stirred for 2 hours at 60° C. 1 ml of carbon tetrachloride is added dropwise and the mixture is stirred for a further 3 hours at 60° C. The solvent is removed under reduced pressure and the remaining oil is chromatographed over silica gel. Yield: 2.4 g (57% of theory), Rf value: 0.32 (silica gel; cyclohexane/ethyl acetate=4:1)
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[C:7]1([NH:13]C2C=CC=CC=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[NH:13]1[C:7]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:2](=[O:3])[C:1]1=[O:5]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C1Nc2ccccc2C1=O

Procedure:
A solution of oxalyl chloride (175 mL, 254.6 g, 2.01M) was cooled to 5°, and a solution of diphenylamine (320 g, 1.89M) in toluene (580 mL) added over 8 minutes. The mixture was heated to 50°-65° for 74 minutes. The mixture was then heated to 125° to distill toluene and excess oxalyl chloride; total distillate collected was 630 mL. The solution was then refluxed at 125°±2° for 20 hours to form indoline-2,3-dione. The mixture was cooled to 104°, and a solution of 4-picoline (215 mL, 205.7 g, 2.21M) in acetic acid (750 mL) was added over 17 minutes. The mixture was heated to 130° to remove excess toluene via acetic acid/toluene azeotrope. Additional acetic acid (750 mL) was added during the distillation. A total of 875 mL distillate containing 260 mL toluene was collected. The mixture was cooled to 115°, and acetic anhydride (360 mL, 389.5 g, 3.81M) added over 10 minutes while heating to 120°-130°. The mixture was stirred at 120°±2° for 1.75 hours, and then cooled to 76°. Water (530 mL) was added over 7 minutes followed by isopropanol (430 mL) while maintaining the temperature between 82° and 63°. The mixture was cooled to ambient temperature overnight, then to 0°-5°. The crude product was collected by filtration, washed with isopropanol (2.16 l) and water 1.64 l). Drying in a vacuum oven at 80°-90° yielded the title compound (422.6 g, 75%) as an orange crystalline solid. M.P.: 160.1°-161.9°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.N1C=CC=CC=1.[NH2:32][C:33]1[CH:34]=[C:35]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:36][C:37]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]1>ClCCl>[Cl:50][C:49]1[CH:48]=[CH:47][C:35]([CH2:36][C:37]2([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:39][CH2:38]2)=[CH:34][C:33]=1[NH:32][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(N)c2)CC1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]([C@H](C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
368 mg (1.38 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 15 ml of dichloromethane, 246 mg (1.84 mmol) of 1-chloro-N,N,2-trimethylprop-1-en-1-amine were added and the mixture was then stirred at room temperature for 30 min. 279 μl (3.45 mmol) of pyridine and 324 mg (1.15 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)-cyclopropanecarboxylate were then added, and the reaction mixture was stirred at room temperature for another 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product obtained was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 540 mg of the target compound (88% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+:17](C)(C)N.CC(C)([O-])C.[K+].[Cl-].[NH4+]>CS(C)=O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([NH2:17])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc([N+](=O)[O-])c2n1
Reactant: C[N+](C)(C)N
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: CS(C)=O
Product: Cc1ccc2ccc(N)c([N+](=O)[O-])c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.8 %

Procedure:
To a solution of 2-methyl-8-nitroquinoline (1.88 g, 10 mmol) and 1,1,1-trimethylhydrazinium iodide (3.03 g, 15 mmol) in anhydrous dimethyl sulfoxide (20 mL) was added potassium tert-butoxide as a solid (3.36 g, 30 mmol). The mixture was stirred at room temperature for 1 h. The mixture was then poured into saturated aqueous ammonium chloride, and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography to give 2-methyl-8-nitroquinolin-7-amine as a yellow solid (300 mg).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)C.[OH-].[K+].C(O)C>O>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:7]1[N:6]([CH2:5][C:4]([OH:21])=[O:3])[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=1
Reactant: CCOC(=O)Cn1c(-c2ccccn2)nc2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1c(-c2ccccn2)nc2cccnc21
Yield: 95.3 %

Procedure:
A solution of 2-(2-pyridinyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (18.0 g, 0.064 mole), potassium hydroxide pellets (5.6 g, 0.100 mole), 95% ethanol (250 ml) and water (10 ml) was refluxed for 11/2 hr. The solution was evaporated to 1/3 volume and then diluted with water (50 ml) and acidified with glacial acetic acid. Water (200 ml) was added and the mixture filtered after precipitation was complete, giving 15.5 g (96%) of a granular solid. Recrystallization of a 2.0-g portion twice from ethanol-water gave 1.5 g of an off-white granular solid, mp 224°-225° C. with decomposition.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1>>[Br:1][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1)[C:11]([OH:13])=[O:12]
Reactant: BrBr
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(O)C(Br)c1ccc(Cl)cc1

Procedure:
In a stirred reactor with reflux condenser (connected to a caustic scrubber) 171 g 4-chlorophenyl acetic acid are pre-charged in 400 g chlorobenzene and heated to 105° C. Within 30 minutes 42 g thionyl chloride is added at 105-110° C. to form partly the acid chloride. To the reaction mixture 256 g bromine (1.6 mole) are added within 90 minutes at 105-108° C. The reaction mixture is stirred for another 2-3 hour at 105-108° C. until the conversion of the 4-chlorophenyl-acetic acid is complete (control by HPLC). Excess bromine is distilled off as a bromine/chlorobenzene mixture at 90° C. until a vacuum of 250 mbar is reached and the colour of the reaction mixture has changed from brown to yellow. The bromine distillate can be re-used in the next batch. The reaction mixture, containing a mix of bromo-(4-chloro-phenyl)acetic acid and acid chloride is diluted with chlorobenzene to a weight of 800 g and can directly be converted to (4-chloro-phenyl)-prop-2-ynyloxy-acetic acid according to Example 14.
Reaction SMILES: [CH3:1][C@@:2]([NH:15][NH2:16])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([OH:10])[CH:9]=1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:19]=1[C:20](Cl)=[O:21]>FC(F)(F)C(O)=O>[C:12]([C:2]([NH:15][NH2:16])([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[C:8]([O:10][C:20](=[O:21])[C:19]2[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:18]=2[CH3:17])[CH:9]=1)([OH:14])=[O:13]
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NN)C(=O)O
Reactant: Cc1cccc(C)c1C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1C(=O)Oc1cc(CC(C)(NN)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
To a solution of carbidopa (732 mg, 3 mmol) in trifluoroacetic acid (10 mL), was slowly added 2,6-dimethyl-benzoyl chloride (504 mg, 3 mmol) at 0° C. and the mixture stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The oily residue was dissolved in acetonitrile/H2O and purified by reverse phase preparative HPLC to afford 196 mg of compound 125 [1H NMR (CD3OD, 400 MHz) 1.49 (s, 3H), 2.45 (d, 6H), 3.10 (dd, 2H), 6.82–7.25 (m, 6H). MS (ESI) m/z 359.23 (M+H+)] and 161 mg of compound 126 [1H NMR (CD3OD, 400 MHz): 1.45 (s, 3H), 2.42 (d, 6H), 3.15 (dd, 2H), 6.74–7.27 (m, 6H). MS (ESI m/z 359.23 (M+H+)].
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)N.[CH:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)C.O>[CH2:17]([C:16]1[C:14]2[C:4](=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:13]=2)[NH:2][CH:15]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)c1ccc(NN)cc1
Reactant: CCCCCC=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCc1c[nH]c2ccc(C(=O)OCC)cc12
Temperature: 100 °C
Yield: 7.1 %

Procedure:
To a mixture of ethyl 4-hydrazinobenzoate hydrochloride (10 gm) in ethanol:water (5:1 100 mL) was added hexanal (4.62 gm). The mixture was refluxed at 100° C. for 3 h. The solvents were removed and toluene (100 mL) and p-toluene sulfonic acid (0.1 g) were added. The mixture was refluxed at 120° C. for 18 h, cooled to room temperature and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 90:9:1 (hexanes: methylene chloride: ethyl acetate) as eluent to give 0.8 g of the title compound: 1H NMR (CDCl3) δ 0.957, 1.44, 1.72, 2.78, 4.40, 7.02, 7.34, 7.90, 8.13, 8.38.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CO.[N+]([O-])(O)=[O:15].NC(N)=O>CC(C)=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:15])[CH2:1]1
Reactant: O=[N+]([O-])O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: NC(N)=O
Solvent: CO
Solvent: CC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Yield: 125 %

Procedure:
A solution of 5.0 g. of acetonine in 21 g. of methanol was added with 19 g. of acetone and 4.0 g. of urea nitrate. The mixture was maintained at room temperature for 24 hours to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 125%.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]4[N:27](C5CCCCO5)[N:28]=[CH:29][C:22]=34)=[CH:16][CH:15]=2)=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>CCOCC>[C:1]1([CH2:7][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]4[NH:27][N:28]=[CH:29][C:22]=34)=[CH:18][CH:19]=2)=[S:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3[nH]ncc23)cc1
Yield: 100.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 2-phenyl-N-{[(4-{[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]oxy}phenyl)amino]-carbonothioyl}acetamide (0.070 g, 0.14 mmol, 1.0 eq.) and 4M HCl/Dioxane (5 ml). After 5 minutes ether was added. The resulting solid was filtered and washed twice with ether. The solid was further dried under vacuum to give 2-phenyl-N-({[4-(1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)phenyl]amino}carbonothioyl)acetamide (0.057 g, 96% yield). 1H NMR (400 MHz, DMSO): 12.40 (s, 1H), 11.79 (s, 1H), 8.52 (s, 1H), 8.14 (s, 1H), 7.71 (d, 2H), 7.33 (m, 8H), 3.83 (s, 2H); MS (ESI) for C20H16N6O2S: 403 (MH+).
Reaction SMILES: CN1CCOCC1.[C:8]1([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][NH:31]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:21]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCCc1ccccc1
Temperature: -25 °C
Reaction time: 16 h
Yield: 87.9 %

Procedure:
N-Methylmorpholine (3.4 ml) and 4-phenylbutyric acid (5.02 g) were added to L-proline benzyl ester hydrochloride (7.37 g) in dichloromethane (80 ml) under ice-cooling. The mixture was cooled to -25° C., added with DCC (6.31 g) and stirred at room temperature for 16 hours. The resultant dicyclohexylurea was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluate: chloroform-methanol) to give 9.42 g of N-(4-phenylbutyryl)-L-proline benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>CO.CC(OC)(C)C.Cl[Pd]Cl>[ClH:1].[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:14]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1F
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)cc2F)c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
Methyl 2-chloroisonicotinate (2.8 g, 16.32 mmol), 2-fluoro-4-(trifluoromethyl)phenylboronic acid (5.09 g, 24.48 mmol), potassium carbonate (1.692 g, 12.24 mmol) and PdCl2 (dppf) (0.354 g, 0.49 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a dark-orange solid. The solid was dissolved in MTBE and stirred for 15 minutes, then filtered. The orange MTBE layer was treated with hydrogen chloride (4 M in dioxane, 4.08 mL, 16.32 mmol) and stirred for 1 h at room temperature. The precipitate was collected by filtration. Methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)isonicotinate hydrochloride (5.4 g, 99%) was isolated as a slightly orange solid. MS m/z 300 (M+H)+
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[C:28]1([CH2:27][CH2:26][CH2:25][N:17]([CH2:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]2)[C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)CC1
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CN(CCCc2ccccc2)C(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, 0.25 g (6.25 mM) of a 60% suspension of sodium hydride in liquid paraffin was added to a solution of 1.73 g (5.57 mM) of N-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)trifluoroacetoamide in N,N-dimethylformamide (20 ml) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. To this mixture was added 1.0 ml (6.58 mM) of 1-bromo-3-phenylpropane and the mixture was stirred at room temperature for 2.5 hours and further at 60° C. for one hour. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (ethyl acetate-hexane 30%) to provide the title compound.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:29][C:30]1[CH:35]=[C:34](F)[CH:33]=[CH:32][N:31]=1>CN1C(=O)CCC1.O.C(OCC)(=O)C>[Cl:29][C:30]1[CH:35]=[C:34]([O:22][C:20]2[CH:19]=[CH:18][C:16]3[N:17]=[C:13]([NH:12][C@H:8]4[CH2:9][CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7]4)[S:14][C:15]=3[CH:21]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: CCS(=O)(=O)N1CCC[C@H](Nc2nc3ccc(O)cc3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCS(=O)(=O)N1CCC[C@H](Nc2nc3ccc(Oc4ccnc(Cl)c4)cc3s2)C1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a mixture of (S)-2-(1-(ethylsulfonyl)piperidin-3-ylamino)benzo[d]thiazol-6-ol (1.15 g, 3.37 mmol) and cesium carbonate (2.20 g, 6.74 mmole) in 12 ml of NMP was added 2-chloro-4-fluoropyridine (532 mg, 4.05 mmol). The reaction mixture was stirred at 60° C. for 17 hours. The reaction mixture was diluted with water (100 ml) and ethyl acetate (100 ml). The separated organic layer was washed with water (3×50 ml), saturated sodium bicarbonate solution (3×50 ml), water (50 ml), brine (100 ml) and dried over sodium sulfate. Concentration in vacuo and purification by flash chromatography over silica gel with ethyl acetate:hexane (1:1 to 3:1) provided the title compound. Yield: 671 mg. ES/MS m/z 453.0 (MH+), Rt=2.59 min.
Reaction SMILES: C([OH:5])CCC.[CH3:6][C:7]1[CH:12]2[C:13]([CH3:15])([CH3:14])[CH:10]([CH2:11]2)[CH2:9][CH:8]=1.N1C=CC=CC=1.OO>>[CH3:14][C:13]1([CH3:15])[CH:12]2[C:7]3([CH3:6])[O:5][CH:8]3[CH2:9][CH:10]1[CH2:11]2
Reactant: CCCCO
Reactant: CC1=CCC2CC1C2(C)C
Agent: OO
Solvent: c1ccncc1
Product: CC1(C)C2CC3OC3(C)C1C2
Temperature: 49.85000000000002 °C
Reaction time: 0.65 h

Procedure:
48 ml of n-butanol (525 millimols), 152 ml of alpha-pinene (975 millimols), 1.15 ml of pyridine (14 millimols) and 807 mg of SeO2 (7.3 millimols) are introduced successively into a reactor similar to that of Example 1. The Florentine receiver itself contains 25 ml of n-butanol (273 millimols). After the reaction mixture has been heated to a temperature of 323 K., 10 ml of 84% strength H2O2 (340 millimols) are introduced over a period of 25 minutes. After the reaction has been left to continue for a further 39 minutes, the alpha-pinene oxide formed is determined by gas chromatography: 292 millimols.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:11][C:10](=[CH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl>[C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:9][C:10]2([O:22][CH2:12]2)[CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1CC(NC(=O)OC(C)(C)C)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC2(CO2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
A solution of (3-methylene-cyclobutyl)-carbamic acid tert-butyl ester (4.27 g, 23.3 mmol) in dichloromethane (95 mL) was cooled to 0° C. in an ice/water bath. 3-Chloroperbenzoic acid (77% technical grade, 5.84 g, 26 mmol) was added in small portions. After stirring at 0° C. for 1.5 hours, the mixture was transferred to a separatory funnel and washed sequentially with 10% aqueous Na2SO3 (50 mL), saturated aqueous NaHCO3 (30 mL), and saturated aqueous NaCl (30 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 30-100% ethyl acetate in heptane), affording the title compound (2.84 g, 61%) as a white solid. NMR showed a 1:1 mixture of N,O-cis/trans isomers. 1H NMR (400 MHz, chloroform-d) δ ppm 1.46 (d, J=1.26 Hz, 9H) 2.35-2.45 (m, 2H) 2.67-2.83 (m, 4H) 3.97-4.36 (m, 1H) 4.77 (br. s., 1H)
Reaction SMILES: CC(C1C=CC(CC(=O)CC)=CC=1)(C)C.C(O)(=O)/C=C\C(O)=O.C1C2CCC3C=CC=CC=3C(=[C:39]3[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][C:48]([C:50]4[CH:55]=[CH:54][C:53]([C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:51]=4)=[O:49])[CH2:41][CH2:40]3)C=2C=CC=1.[CH:60]1[C:70]2[CH:69]([OH:71])[C:68]3[CH:72]=[CH:73][CH:74]=[CH:75][C:67]=3[CH2:66][O:65][C:64]=2[CH:63]=[CH:62][CH:61]=1>CCOCC>[CH3:59][C:56]([C:53]1[CH:54]=[CH:55][C:50]([CH:48]([OH:49])[CH2:47][CH2:46][CH2:45][N:42]2[CH2:41][CH2:40][CH:39]([C:69]3([OH:71])[C:68]4[CH:72]=[CH:73][CH:74]=[CH:75][C:67]=4[CH2:66][O:65][C:64]4[CH:63]=[CH:62][CH:61]=[CH:60][C:70]3=4)[CH2:44][CH2:43]2)=[CH:51][CH:52]=1)([CH3:57])[CH3:58]
Reactant: CC(C)(C)c1ccc(C(=O)CCCN2CCC(=C3c4ccccc4CCc4ccccc43)CC2)cc1
Reactant: OC1c2ccccc2COc2ccccc21
Agent: CCC(=O)Cc1ccc(C(C)(C)C)cc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C(O)CCCN2CCC(C3(O)c4ccccc4COc4ccccc43)CC2)cc1

Procedure:
By procedures essentially the same as those described in Example 2, and by substituting 4-[4-(6,1]-dihydro-11-hydroxydibenz[b,e]oxepin-11-yl)-1-piperidinyl]-1-[4-(1,1-dimethylethyl)phenyl]butanone for 4-[4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]-1-[4-(1,1-dimethylethyl)phenyl]-1-butanone maleate; the corresponding 11-[1-[4-[4-(1,1-dimethylethyl)phenyl]-4-hydroxybuty]]-4-piperidinyl]-6,11-dihydrodibenz[b,e]oxepin-11-ol, mp 135°-137° C. and 162-165° C. (ether), was prepared.
Reaction SMILES: COC1C=CC(C2(C3N4N=C(C5C=CC=CC=5)C=NC4=NN=3)CC2)=CC=1.C[O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([C:38]3[N:42]4[N:43]=[CH:44][C:45]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)=[N:46][C:41]4=[N:40][N:39]=3)[CH2:37][CH2:36]2)=[CH:31][CH:30]=1.B(Br)(Br)Br>C(Cl)Cl>[C:47]1([C:45]2[CH:44]=[N:43][N:42]3[C:38]([C:35]4([C:32]5[CH:31]=[CH:30][C:29]([OH:28])=[CH:34][CH:33]=5)[CH2:37][CH2:36]4)=[N:39][N:40]=[C:41]3[N:46]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: COc1ccc(C2(c3nnc4nc(-c5ccccc5)cnn34)CC2)cc1
Agent: BrB(Br)Br
Agent: COc1ccc(C2(c3nnc4ncc(-c5ccccc5)nn34)CC2)cc1
Solvent: ClCCl
Product: Oc1ccc(C2(c3nnc4nc(-c5ccccc5)cnn34)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-[1-(4-methoxyphenyl)cyclopropyl]-6-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine (17.0 mg, 0.0495 mmol) and 3-[1-(4-methoxyphenyl)cyclopropyl]-7-phenyl[1,2,4]triazolo[4,3-b][1,2,4]triazine (17.0 mg, 0.0495 mmol) in DCM (3.0 mL) was added 1.00 M of boron tribromide in DCM (0.5 mL). The mixture was stirred at RT for 3 h. The solvent was evaporated. The residue was diluted with methanol (5 mL). The resulting mixture was subject to preparative RP-HPLC to give the two regioisomers. Analytical LCMS: (M+H)+=330.1. Isomer-I: Rt=1.451 min; Isomer-II: Rt=1.450 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14](C)C>>[O:10]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:9][CH:13]=[N:14]1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(O)cc1
Product: Oc1ccc(-c2ccno2)cc1

Procedure:
1-(4-hydroxyphenyl)ethanone (5 g, 36.7 mmol) was heated in dimethylformamide dimethyl acetal (6.56 g, 55 mmol) at 100° C. overnight. The solution turned dark red. Volatile solvent was removed under high vacuum. The crude 3-(dimethylamino)-1-(4-hydroxyphenyl)prop-2-en-1-one was dissolved in ethanol, followed by addition of hydroxylamine hydrochloride salt. The mixture was heated under reflux for 3 hours. The solvent was removed under vacuum. The residue was purified twice by column chromatography through 120 g biotage silica gel cartridges eluting with 10-40% EtOAc/hexanes (gradient) and 20% ethyl acetate/hexanes (isocratic) to give the product as white solid. LRMS calc: 161.1; obs: 162.2 (M+1).