Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([CH3:32])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C@@H:20]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH2:15]2)=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[K+].[ClH:36]>C(O)C.O1CCCC1.C(OCC)(=O)C>[ClH:36].[CH3:6][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C@@H:20]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH2:15]2)=[CH:10][CH:9]=1)([CH3:32])[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc([C@@H]2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](N[C@H]1CC[C@@H](c2ccc(OC(C)(C)C(=O)O)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
2-Methyl-2-{4-[(1R,3S)-3-{[(1R)-1-(naphthalen-1-yl)ethyl]amino}cyclopentyl]phenoxy}propanoic acid ethyl ester (130 mg, 0.29 mmol) was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL), followed by addition of 2N aqueous potassium hydroxide solution, and the mixture was stirred overnight at room temperature. 1N hydrochloric acid was added dropwise to the reaction mixture to make the reaction solution acidic, and the solvent was distilled off under reduced pressure. The aqueous phase was extracted with ethyl acetate, the extracted solution was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue obtained was dissolved in ethyl acetate (3 mL), followed by addition of an ethyl acetate solution of 1N hydrochloric acid (1 mL), and the solvent was distilled off under reduced pressure. Ethyl acetate and hexane were added to the residue, followed by treatment with ultrasonic waves, and then the solid matter generated was collected by filtration to give the title compound (102 mg, 77%).
Reaction SMILES: [SH:1][C@H:2]1[N:5]([C:6](=[C:19]([CH3:21])[CH3:20])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:22])[C@@H:3]1[Br:23].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C.[Ag]>[CH2:24]([S:1][C@H:2]1[N:5]([C:6](=[C:19]([CH3:20])[CH3:21])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:22])[C@@H:3]1[Br:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(COC(=O)C(=C(C)C)N2C(=O)[C@H](Br)[C@H]2S)cc1
Agent: [Ag]
Solvent: CC#N
Product: COc1ccc(COC(=O)C(=C(C)C)N2C(=O)[C@H](Br)[C@H]2SCc2ccccc2)cc1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
A solution of the silver salt of p-methoxybenzyl 2-[(3S, 4R)-4-mercapto-3-bromo-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (10 g, 20 mmol) in dry acetonitrile (100 ml) was treated with benzyl bromide (4 g, 24 mmol) and the resulting mixture refluxed for 30 mins. the reaction was cooled to room temperature, filtered, evaporated to dryness and the residue purified by flash chromatography using 1:1 ether:pentane as the eluting solvent. Evaporation of the appropriate fractions gave the product as a white solid (5.8 g, 59%), mp 70-72° C. 1H NMR δ (CDCl3)1.93 (3H, s, CH3), 2.23 (3H, s, CH3), 3.66 (1H, dd, J=2.9, 17.5 Hz, SCH2), 3.79 (3H, s, OCH3), 4.52 (1H, d, J=1.8 Hz, H3), 4.95 (1H, d, J=1.9 Hz, H4), 5.08 (2H, q, J=12.0 Hz, CO2CH2), 6.84-6.90 (2H, m, 2.6Ph--H), 7.13-7.31 (7H, m, 3,5Ph--H,Ph--H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].[CH3:11][N:12]=[C:13]=[O:14]>C1C=CC=CC=1>[CH3:10][C:6]1[C:3]([CH2:4][OH:5])=[C:2]([NH:1][C:13]([NH:12][CH3:11])=[O:14])[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cccc(N)c1CO
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)Nc1cccc(C)c1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
A mixture of 2-amino-6-methylbenzyl alcohol (0.274 g) and methyl isocyanate (0.11 g) in benzene (5.2 ml) was stirred at room temperature for 15 minutes. The resulting precipitates were collected by filtration and dried to give 6-methyl-2-(3-methyl ureido)benzyl alcohol (0.24 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:10]([O:13]C(=O)C)[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([Mg]Cl)[CH:25]([CH3:27])[CH3:26]>C1COCC1.CCOCC.CO.[H][H]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:10]([OH:13])[C@@H:11]([OH:12])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC(C)C[Mg]Cl
Reactant: CC(=O)O[C@@H](C=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 2 h

Procedure:
The oil prepared in Step 1 was dissolved under nitrogen in 100 mL of dry THF and cooled to -70° C. To this solution was added 13 mL (26 mmol) of a 2.0 M solution of isobutylmagnesium chloride in ether and the stirred mixture was allowed to warm to room temperature and stir for 2 hrs. After decomposition with MeOH/H2 the mixture was diluted with ether, washed with saturated NH4Cl solution twice, then dried and the solvents stripped off under vacuum. The residue was allowed to stand overnight in 80% MeOH-H2O containing excess ammonium hydroxide. The MeOH was stripped off and the mixture was extracted with ether. These extracts were combined, washed with water, dilute KHSO4, then dried and evaporated to give 2.36 g of a yellow glass which crystallized from 50 mL of pentane on standing overnight. The yellow-white powder obtained was recrystallized from ether-hexane and furnished the title compound (0.41 g) as white, hairy needles, mp 134°-136° C., Rf (ether): single spot, 0.6. By chromatography of the mother liquors and crystallization of the appropriate fractions, an additional 0.22 g of product, mp 138°-139° C., was obtained. Anal: Calcd. for C19H31NO4 (337.45): C, 67.62; H, 9.26; N, 4.15. Found: C, 67.51; H, 9.43; N, 4.24.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([Li])CCC.Cl[CH2:13][C:14]1[CH:30]=[CH:29][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[O:19])=[CH:16][CH:15]=1.C1COCC1>CCOCC.O>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:30][CH:29]=1
Reactant: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Reactant: C1COCCN1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1NC(=O)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.2 %

Procedure:
In an atmosphere of argon, morpholine (192 mg, 2.2 mmol) was dissolved in ether (5 ml) to which, with cooling in an ice bath, was subsequently added n-butyl lithium (1.45 ml, 1.52M, 2.2 mmol). After 5 minutes of stirring at room temperature, to this was added 4-chloromethyl-N-(2-methoxyphenyl)benzamide (276 mg, 1.0 mmol) at the same temperature. After adding THF (5 ml) and stirring for 2.5 hours at 60° C., the reaction solution was mixed with water (20 ml) and extracted with ethyl acetate. After removing insoluble materials by filtration, the organic layer was washed with water and saturated brine and then dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation, and the resulting residue was purified by subjecting it to a silica gel column chromatography (ether) to obtain 128 mg (39.2%) of the title compound in the form of light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-])=[CH:9]2)=[CH:4][C:3]=1[F:13].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:9]1[C:10]2[C:5](=[CH:4][C:3]([F:13])=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc2cc(F)c(Cl)cc2c1
Product: Fc1cc2ccnc(Cl)c2cc1Cl
Temperature: 25 °C

Procedure:
2.6 g (12.0 mmol) of 7-Chloro-6-fluoro-isoquinoline 2-oxide (57) were heated in 40 ml of POCl3 at reflux for 4 h. After the mixture has cooled down to room temperature, it was poured on ice. The aqueous solution was extracted three times with dichloromethane. The combined organic layers were dried with MgSO4 and evaporated to yield 2.91 g of the title compound, which was used without further purification. Rt=2.34 min (Method A). Detected mass: 216.0/218.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([OH:12])=[CH:5]2.O[CH:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1.PPP.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][CH:18]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17]1)=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1cnc2ccc(Br)cc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: PPP
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cnc3ccc(Br)cc3c2)C1
Temperature: 50 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
To a solution of 6-bromoquinolin-3-ol (500 mg, 2.232 mmol), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (418 mg, 2.232 mmol) and triphosphine (875 mg, 3.35 mmol) in THF (10 ml) was added DEAD (0.424 ml, 2.68 mmol) at 0° C. Then the mixture was stirred at 50° C. for 6 h under N2. The mixture was diluted with ether and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluted with Hex/EA (from 100% to 95%) to afford the title compound (650 mg, 67% yield) as brown gel.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([OH:28])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[Cl-].[C:32]1([N:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:39]([N+]2C=CC=CC=2)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][C:39](=[O:40])[N:38]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(N(c1ccccc1)c1ccccc1)[n+]1ccccc1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC(=O)N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 110.2 %

Procedure:
A solution of 3.99 g of 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5-hydroxymethylimidazole (Example 94) and 10 mL of 1.00N aqueous sodium hydroxide in 60 mL of methanol was added dropwise over 0.25 hour to a solution of 3.73 g of N-(N,N-diphenylcarbamoyl)pyridinium chloride in 30 mL of methanol at 25° C. The resulting mixture was stirred at 25° C. for 0.75 hour and then was diluted with ethyl acetate. This organic solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 6.55 g of crude 2-butyl-4-chloro-1-[(2'-(N,N-diphenylcarbamoyloxycarbonyl)biphenyl-4-yl)methyl]-5-hydroxymethylimidazole which was used in the following step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:4]1([CH2:7][CH3:8])[CH2:6][CH2:5]1)=[O:3].[CH:9](=O)[C:10]1[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[C:12]([O:13][CH3:14])[CH:11]=1>>[CH2:7]([C:4]1([C:2]([CH:1]=[CH:9][C:10]2[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[C:12]([O:13][CH3:14])[CH:11]=2)=[O:3])[CH2:6][CH2:5]1)[CH3:8]
Reactant: CCC1(C(C)=O)CC1
Reactant: COc1ccc(C=O)cc1OC
Product: CCC1(C(=O)C=Cc2ccc(OC)c(OC)c2)CC1

Procedure:
2-(3,4-Dimethoxyphenyl)vinyl 1-ethylcyclopropyl ketone [III; Ar is 3,4-(CH3O)2C6H3, R is C2H5 ] was prepared from 22.4 g. of 1-ethylcyclopropyl methyl ketone and 33.2 g. of veratraldehyde according to the procedure described above in Preparation A1, affording 20.3 g., b.p. 156°-158° C. (0.02 mm.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10]CC)=O)=[CH:6][CH:5]=1)[CH3:2].[O-]CC.[Na+].[C:19](#[N:21])[CH3:20]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH2:20][C:19]#[N:21])=[O:10])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OCC)cc1
Reactant: CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc(C(=O)CC#N)cc1
Reaction time: 26 h
Yield: 45 %

Procedure:
Ethyl 4-ethoxybenzoate (45.3 mL, 250 mmole) was added to a suspension of sodium ethoxide (17.0 g, 250 mmole) and acetonitrile (16 mL, 300 mmole) in dry toluene (100 mL) and the mixture was mechanically stirred at 106°-110° for 26 hours. The reaction was then cooled and diluted with water (400 mL). After most of the solid had dissolved, the solution was washed with ethyl ether (2×200 mL) and then acidified with concentrated HCl (approximately 20 mL) to pH of about 5. The copious off-white precipitate was collected by suction filtration and air dried. Crystallization from 95% ethanol (350 mL) provided 21.3 g. of the subtitled compound as white needles, sufficiently pure for further transformation (yield: 45%). 1H NMR (CDCl3, δ) 7.85 (d, 2H, J=8 Hz, o-phenyl), 6.95 (d, 2H, J=8 Hz, m-phenyl), 4.1 (q, 2H, J= 7 Hz, OCH2), 4.0 (s, 2H, CH2CN), 1.45 (t, 3H, CH3).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25][CH2:26][CH:27]([CH2:29]O)[OH:28].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:29][CH:27]([OH:28])[CH2:26][OH:25])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC(O)CO
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(8-cyclohexyloctylamino)benzoic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][O:11][CH3:12])=[CH:7][C:6]([O:13][CH3:14])=[C:5]([O:15][CH2:16][O:17][CH3:18])[C:4]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:29]([O:30][CH2:31][O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=[C:26]([O:36][CH2:37][O:38][CH3:39])[C:25]=1[O:40][CH3:41].CN(C)CCN(C)C.C([Li])CCC.[Br:55]N1C(=O)CCC1=O>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH3:41][O:40][C:25]1[C:26]([O:36][CH2:37][O:38][CH3:39])=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:30][CH2:31][O:32][CH3:33])[C:24]=1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:4]1[C:5]([O:15][CH2:16][O:17][CH3:18])=[C:6]([O:13][CH3:14])[C:7]([Br:55])=[C:8]([O:9][CH2:10][O:11][CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)cc(OC)c2OCOC)c1OC
Reactant: O=C1CCC(=O)N1Br
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OC)c(OCOC)c(Br)c(OC)c2OCOC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
998 Milligrams of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)benzene] was dissolved in a mixed solvent of 30 ml of tetrahydrofuran with 3 ml of hexamethylphosphoric triamide, to this solution was added 1.03 ml of N,N,N',N'-tetramethylethylenediamine, was cooled to -78° C. on a dry ice-acetone mixture bath. 4.56 Milliliters of n-butyllithium (1.6 M, n-hexane solution) was added dropwise to the reaction mixture and stirred for 30 minutes. Next, 15 ml of tetrahydrofuran solution containing 1.22 g of N-bromosuccinimide was added dropwise and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure, and the residue obtained was extracted twice with 50 ml of diethyl ether, and the diethyl ether layer was washed twice with 50 ml of water, and washed twice with 50 ml of a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate. The diethyl ether solution was concentrated under reduced pressure, the residue obtained was purified by means of a preparative thin layer chromatography (thickness: 2 mm, adsorbent: Merck 5717 silica gel, developing solvent: 40% ethyl acetate-n-hexane). There were obtained 155 mg of 1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy- 3,6-bis(methoxymethoxy)-4-bromophenyl]pentane, as well as 22 mg of 2,2'-pentamethylenebis[1,4-dimethoxy-3,6-bis(methoxymethoxy)-5-bromobenzene].
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=O.C([O-])(=O)C.[Na+].[Cl-].O[NH3+:23].C(O)(=O)C>O>[C:14]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:12][C:13]=2[CH:1]=1)#[N:23]
Reactant: [NH3+]O
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc2c(c1)Cc1ccccc1-2
Yield: 63.3 %

Procedure:
25 g of 2-fluorenecarboaldehyde, 11.6 g of sodium acetate, 9.7 g of hydroxy ammonium chloride and 150 ml of acetic acid were stirred at 130 for 18 hours. The reaction mixture was allowed to room temperature, poured into 200 ml of water and the precipitate was collected by filtration. The crude product was purified by column chromatography, giving 15.57 g (63%) of 2-cyanofluorene.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([S:18][C:19]#N)=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[OH-].[K+].Cl>CO.O>[C:12]1([C:11]2[CH:10]=[C:9]([S:18][CH3:19])[NH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#CSc1cc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Solvent: CO
Product: CSc1cc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a mixture of 1.4 g (0.005 mole) 2,3-diphenyl-5-thiocyanatopyrrole, 0.85 g (0.006 mole) methyl iodide in 10 ml methanol was added dropwise at 0° a solution of 0.8 g (~0.012 mole, 85%) potassium hydroxide in 5 ml water+5 ml methanol. The mixture was allowed to warm to room temperature, then was poured into 100 ml ice water and neutralized with hydrochloric acid. The aqueous mixture was extracted with methylene chloride, and the extracts dried and concentrated. The residue was chromatographed on 50 g Silic AR CC-7, eluting with toluene to give 1.2 g (90%) yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[CH2:19][O:20]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[C:37]1(O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>CC#N>[O:20]([CH2:19][C:15]1[O:16][CH:17]=[CH:18][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]
Reactant: Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCc2occc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: c1ccc(OCc2occc2C2CCNCC2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-[2-(Toluene-4-sulfonyloxymethyl)furan-3-yl]piperidine-1-carboxylic acid t-butyl ester (65 mg, 0.15 mmol, 1.0 eq.) was dissolved in MeCN (770 μL) and added to a mixture of potassium carbonate (32 mg, 230 mmol, 1.6 eq.) and phenol (21.1 mg, 224 μmol, 1.5 eq.). The resulting mixture was shaken at 50° C. overnight. The mixture was then cooled and the solids removed. The supernatant was combined with TFA (12 μL, 160 mmol, 1.0 eq.) and the resulting mixture was shaken overnight at room temperature. The solution was concentrated using an evaporator, then dissolved in 1:1 AcOH:H2O (5.0 mL) then an additional 2.0 ml AcOH, filtered, and purified by preparative HPLC to yield the title compound as a TFA salt (1.4 mg, 88% purity). MS m/z: [M+H]+ calcd for C16H19NO2, 258.14. found 258.2.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].FC(F)(F)S(O[CH2:49][C:50]([F:53])([F:52])[F:51])(=O)=O>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:49][C:50]([F:53])([F:52])[F:51])[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(F)(F)F)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2,2,2-trifluoroethyl trifluoromethanesulfonate and isolated as light-yellow solid (3.0 mg, 20%). MS (m/e): 365.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[CH:7][S:8](=O)[C:4]=2[CH:3]=1.C([O-])([O-])=[O:13].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:19][CH2:20][CH2:21][Cl:22])[C:7](=[O:13])[S:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: ClCCCBr
Reactant: O=S1C=Nc2ccc(Cl)cc21
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1sc2cc(Cl)ccc2n1CCCCl
Yield: 93.5 %

Procedure:
A solution of 6-chloro-benzothiazolone (VIII) (55.7 g, 0.3 mol), K2CO3 (62.1 g, 0.45 mol) and 1-bromo-3-chloropropane (IX) (71 g, 0.45 mol) in acetone (600 ml) was refluxed for 16 hours. After cooling, the inorganic substance was filtered off and washed dichloromethane. The filtrate and washings were combined and evaporated in vacuo. The residue was washed with hexane and recrystallized from dichloromethane to obtain compound (X) (73.5 g, yield=93.4%) as colorless needle-shaped crystals.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH:9]1([NH:15][CH:16]2[CH2:22][CH:21]3[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:31]([N:33](CC)[CH2:34][CH3:35])[CH3:32].C(NCC)C>ClCCl>[CH:9]1([N:15]([C:4]([N:33]([CH2:34][CH3:35])[CH2:31][CH3:32])=[O:3])[CH:16]2[CH2:17][CH:18]3[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:21]([CH2:20][CH2:19]3)[CH2:22]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(NC1CCCCC1)C2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.64 ml of diphosgene is placed in 10 ml of dichloromethane at 0° C. under N2. A solution of 1.0 g of tert-butyl 3-(cyclohexylamino)-8-azabicyclo[3.2.1]-octane-8-carboxylate endo compound and 2.26 ml of triethylamine in 10 ml of dichloromethane is added dropwise. The solution is stirred at 0° C. for 30 min and then at ambient temperature for 4 h. 5 ml of triethylamine and 1.0 ml of diphosgene are then added. After stirring at ambient temperature for 2 h, 1.68 ml of diethylamine are added. The mixture is stirred at ambient temperature for 16 h. After concentration, 0.5N hydrochloric acid is added up to an acid pH. Extraction is carried out with dichloromethane until the aqueous phase is completely depleted. The organic phase is washed with H2O, and then with a saturated aqueous sodium chloride solution. After drying over MgSO4 and concentration to dryness, the residue obtained is chromatographed on silica gel, elution being carried out with a 99/1 and then 95/5 mixture of dichloromethane and methanol, to give 1.60 g of tert-butyl 3-{cyclohexyl[(diethylamino)carbonyl]amino}-8-azabicyclo[3.2.1]octane-8-carboxylate as a mixture with diethylurea.