Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH:12](=[O:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CN(C)C=O.O>[CH3:11][O:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[O:1][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:13]([CH2:12][OH:21])=[CH:4]2
Reactant: COc1ccc(O)c(C=O)c1
Reactant: O=CC=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(CO)C(c1ccccc1)O2
Reaction time: 0.25 h
Yield: 47 %

Procedure:
3.8 g (25 mmol) of 2-hydroxy-5-methoxybenzaldehyde are added to a solution of 3.63 g (27.5 mmol) of cinnamaldehyde in 25 ml of N,N-dimethylformamide; 3.8 g (27.5 mmol) of potassium carbonate are then added to the medium. After 10 minutes of reflux, the reaction mixture is concentrated in vacuo; the residue is then taken up in water. The aqueous phase is extracted with ethyl acetate; the organic phase is then dried over magnesium sulphate. After evaporation of the solvent in vacuo, the crude product is dissolved in 30 ml of anhydrous ethanol; 0.95 g (25 mmol) of sodium borohydride is then added to the medium. The solution is stirred under argon for 15 minutes; the solvent is then evaporated in vacuo. The residue obtained is dissolved in water and then hydrolysed with a 1N hydrochloric acid solution. The aqueous phase is extracted with ethyl acetate; the organic phase is then dried over magnesium sulphate. After evaporation of the solvent in vacuo, chromatography on a silica column (eluant: AcOEt/PE: 30/70 then 40/60) yields the title alcohol in the form of a yellow solid in a yield of 47%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C@@H:16]3[C@@H:12]([CH2:13][O:14][CH2:15]3)[O:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][C:21]([F:34])([F:33])[CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:17][C:10]1[O:11][C@H:12]2[C@@H:16]([C@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:30]([C:27]4[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:21]([F:34])([F:33])[F:20])=[CH:29][N:28]=4)=[O:31])[CH:3]=[CH:4][C:5]=3[F:19])([CH3:18])[N:9]=1)[CH2:15][O:14][CH2:13]2
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)F)cn3)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21

Procedure:
The coupling of (3aS,7S,7aS)-7-(5-amino-2-fluoro-phenyl)-7-methyl-3,3a,7,7a-tetrahydro-1H-2,4-dioxa-6-aza-inden-5-ylamine and 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (prepared as described in Banner D. et al., WO 2010/128 058) following procedure G yielded the title compound as a colorless solid. MS: m/z=469.2 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[CH:7][C:6]=2[CH:11]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:11][C:6]=2[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cc(I)ccc2o1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc2cc(I)ccc2o1
Reaction time: 0.75 h
Yield: 49 %

Procedure:
To a carbon tetrachloride (28 mL) solution of 5-iodo-2-methylbenzofuran (500 mg, 1.94 mmol) were added N-bromosuccinimide (410 mg, 2.3 mmol) and 2,2-azobis(isobutyronitrile) (47.8 mg, 0.291 mmol). This mixture was stirred for 2 hours and 45 minutes while heating under reflux. After allowing the reaction mixture to cool on standing, the reaction mixture was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2-bromomethyl-5-iodo-benzofuran (320 mg, 49%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C@H:12]2[CH2:24][C@H:23]3O[C@@:22]3(C)[C@@H:13]2[C@H:14]([O:17][C:18](=[O:21])[NH:19][CH3:20])[O:15][CH:16]=1)=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:8][C:9]([C:11]1[CH:12]2[CH2:24][CH2:23][CH2:22][CH:13]2[CH:14]([O:17][C:18](=[O:21])[NH:19][CH3:20])[O:15][CH:16]=1)=[O:10]
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)OCc2ccccc2)[C@H]2C[C@H]3O[C@@]3(C)[C@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNC(=O)OC1OC=C(C(=O)OC)C2CCCC12
Reaction time: 24 h
Yield: 75.1 %

Procedure:
1.35 g of (1S,4aS,6R,7S,7aR)-6,7-epoxy-7-methyl-1-(methylcarbamoyloxy)-1,4a,5,7a-tetrahydrocyclopenta[c]pyrane-4-carboxylic acid benzylester described in Step 5 of Example 1 were dissolved in ethyl acetate followed by suspension of 60 mg of 5% palladium-carbon catalyst and stirring for 24 hours under hydrogen gas atmosphere at 1 atm. After filtering out the insoluble matter, the filtrate was concentrated. The residue was dissolved in methanol-ether followed by dropwise addition of 3.0 ml of trimethylsilyldiazomethane (2.0 M, hexane solution) and stirring for 30 minutes at room temperature. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the hexane-ether eluate in the form of (1S,4aS,6R,7S,7aR)-6,7-epoxy-7-methyl-1-(methylcarbamoyloxy-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyrane-4-carboxylic acid methylester (720 mg, yield: 68%). The physicochemical properties of this compound are described in Table 12, Compound No. 57.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[CH:54][C:55]4[N:60]([S:61]([CH3:64])(=[O:63])=[O:62])[CH2:59][CH2:58][O:57][C:56]=4[N:65]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[CH3:64][S:61]([N:60]1[CH2:59][CH2:58][O:57][C:56]2[N:65]=[C:52]([C:49]3[CH:48]=[CH:47][C:46]([C:42]4([NH2:41])[CH2:45][CH2:44][CH2:43]4)=[CH:51][CH:50]=3)[C:53]([C:66]3[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=3)=[CH:54][C:55]1=2)(=[O:63])=[O:62]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(S(C)(=O)=O)CCO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: CS(=O)(=O)N1CCOc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 126.3 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(1-(methylsulfonyl)-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (45 mg, 0.08 mmol) was reacted to afford the title compound (44 mg, 95%). LCMS (Method A): RT=2.34 min, M+1=437. 1H NMR (500 MHz, MeOD): 8.15 (1H, s), 7.43-7.38 (4H,m), 7.30-7.28 (3H, m), 7.21-7.19 (2H, m), 4.57 (2H, t), 4.01 (2H, t), 3.19 (3H, s), 2.79-2.73 (2H, m), 2.60-2.54 (2H, m), 2.24-2.21 (1H, m), 1.99-1.94 (1H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=2[CH3:23])=[CH:9][C:8]=1[CH3:24])[CH3:2].[F:26][C:27]([F:36])([F:35])[C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:32][C:31]3[CH:33]=[CH:34][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:29][CH:30]=3)=[CH:17][C:16]=2[CH3:23])=[CH:9][C:8]=1[CH3:24])[CH3:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)COc1cc(C)c(Sc2ccc(C=O)cc2C)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)COc1cc(C)c(Sc2ccc(CNc3ccc(C(F)(F)F)cc3)cc2C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a stirred solution of compound 21.4 (13.5 g, 37.7 mmol) in CHCl3 (135 mL) was successively added 4-(trifluoromethyl)aniline (6.07 g, 37.7 mmol) and AcOH (3.24 mL). After stirring at room temperature for 30 min, the reaction was cooled to 0° C., sodium triacetoxyborohydride (12.0 g, 56.6 mmol) was added, and the reaction was stirred at room temperature for 3 h. The reaction mixture was poured into 150 mL of ice-water and the product was extracted with 2×50 mL CHCl3. The organics were sequentially washed with 150 mL aqueous NaHCO3 and 150 mL brine, dried over MgSO4, and concentrated to a yellow oil, which was purified with flash chromatography (SiO2 gel 60 N, eluted with 10% EtOAc/hexanes-20% EtOAc/hexanes). The fractions containing the desired product were combined and concentrated to yield a colorless solid (18.7 g). 1H NMR (400 MHz) (CDCl3) δ 7.38 (2H, d, J=8.5 Hz); 7.20 (1H, s); 7.14 (1H, s); 6.97 (1H, d, J=8.1 Hz); 6.70-6.50 (4H, m); 4.66 (2H, s); 4.40-4.20 (5H, m); 2.38 (3H, s); 2.30 (3H, s); 2.22 (3H, s); 1.31 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CCc2ccccc2)S(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
To [6-methoxy-2′-(phenethylamino-methyl)-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester (0.068 g, 0.15 mmol) and triethylamine (0.02 mL, 0.16 mmol) in CH2Cl2 (1 mL) was added methanesulfonyl chloride (0.01 mL, 0.16 mmol), and the mixture was stirred for 1 hour. Starting material was still present by analytical LCMS, so additional methanesulfonyl chloride was added, and the reaction was stirred overnight at room temperature. Additional methanesulfonyl chloride and triethylamine was added after 20 hours to push the reaction to completion. The solution was then diluted with CH2Cl2 and H2O, and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:19])[CH:12]=[CH:11][C:10]=1[C:20]([CH3:22])=[CH2:21])C1C=CC=CC=1>[C].[Pd].C(O)C>[CH:20]([C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[C:17]([CH3:19])[CH:16]=[CH:15][CH:14]=2)[C:9]=1[OH:8])([CH3:22])[CH3:21]
Reactant: C=C(C)c1ccc2cccc(C)c2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc2ccc(C(C)C)c(O)c12
Yield: 93.6 %

Procedure:
1.0 g of 1-benzyloxy-2-isopropenyl-8-methylnaphthalene and 0.1 g of 10% palladium-carbon (water content of 50%) were added to 40 ml of ethanol and hydrogenated at normal temperatures and normal pressures. The palladium-carbon was filtered through Celite, after which the filtrate was concentrated under reduced pressure to obtain 0.65 g of the captioned compound as a black oily substance.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9](/[CH:11]=[CH:12]/[C:13]([O:15]CC)=[O:14])[CH:8]=[CH:7][C:6]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.Cl>CO.C1COCC1>[CH3:3][O:4][C:5]1[N:10]=[C:9](/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:8]=[CH:7][C:6]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1
Reactant: CCOC(=O)/C=C/c1ccc(-n2cnc(C)c2)c(OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A 5 N sodium hydroxide solution (4 mL) was added to a solution of ethyl (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylate (1.5 g) in methanol (10 mL) and THF (6 mL). The reaction solution was stirred at room temperature for two hours, and then 5 N hydrochloric acid (5 mL) was added to the reaction solution. The generated precipitate was filtered and washed with THF to obtain 755 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Mg].Br[CH2:3][CH3:4].[F:5][C:6]([F:15])([F:14])[CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1.S(=O)(=O)(O)O>C1COCC1>[CH2:3]([C:10]1([OH:13])[CH2:11][CH2:12][CH:7]([C:6]([F:14])([F:15])[F:5])[CH2:8][CH2:9]1)[CH3:4]
Reactant: CCBr
Reactant: O=C1CCC(C(F)(F)F)CC1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC1(O)CCC(C(F)(F)F)CC1
Temperature: -5 °C
Yield: 70 %

Procedure:
The inside of a reactor was sufficiently dried by vacuum heating, and the atmosphere inside the reactor was replaced with dry nitrogen. The reactor was charged with a Grignard reagent that was prepared in 350 ml of dehydrated tetrahydrofuran (dehydrated THF) using 9.7 g (0.40 mol) of a magnesium powder and 38.9 g (0.36 mol) of bromoethane 50 ml of a dehydrated THF solution of 49.8 g (0.30 mol) of 4-trifluoromethylcyclohexanone was added to the reactor over 15 minutes with stirring while cooling the solution at −5° C. using an ice bath. After increasing the temperature of the reactor to room temperature, the mixture was stirred for 2 hours. 500 ml of ice water and 100 ml of ice-cooled diluted sulfuric acid were then added to the mixture while sufficiently stirring the mixture. After separating the THF layer, the aqueous layer was extracted with diethyl ether to obtain an extract. The extract was combined with the THF layer, sequentially washed with a 5% sodium carbonate aqueous solution and water, and dried over sodium sulfate (desiccating agent). After removing sodium sulfate using a Buchner funnel, the organic solvent was evaporated. The residue was distilled under reduced pressure (30 mmHg). 1-Ethyl-4-trifluoromethylcyclohexanol was thus obtained (41.2 g (yield: 70%)).
Reaction SMILES: [C:1]([N:4]([CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]3[CH2:40][CH2:39][S:38](=[O:42])(=[O:41])[CH2:37][CH2:36]3)=[C:31]([F:43])[CH:30]=2)[CH2:24]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:21])[C@@H:11]([NH:13]C(OC(C)(C)C)=O)[CH3:12])=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.[ClH:52]>C1COCC1>[ClH:52].[C:1]([N:4]([CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]3[CH2:40][CH2:39][S:38](=[O:41])(=[O:42])[CH2:37][CH2:36]3)=[C:31]([F:43])[CH:30]=2)[CH2:24]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:21])[C@@H:11]([NH2:13])[CH3:12])=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: COc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a mixture of the 2(S)-tert-butoxycarbonylamino-propionic acid (acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamoyloxy)-methyl ester (12b) (0.98 g, 1.56 mmol), anisole (1 mL) and THF (30 mL), is added hydrogen chloride (4 M in dioxane, 11 mL, 46.8 mmol) in a dropwise manner. The mixture is stirred at RT overnight. Under reduced pressure, the mixture is concentrated to one-half of its original volume. Ether is then added dropwise to the mixture while stirring, resulting in the formation of a solid. The solid is collected via filtration, rinsed with ether and ethyl acetate, and dried under vacuum to give the title compound in 38% yield (0.34 g). 1H NMR (400 MHz, CD3OD): δ 7.51 (dd, 1H), 7.37 (t, 1H), 7.26 (dd, 1H), 6.02 (ABq, 2H), 4.87 (m, 1H), 4.29 (app q, 1H), 4.19 (m, 2H), 4.10 (dd, 1H), 3.83 (dd, 1H), 3.37 (m, 2H), 3.23 (tt, 1H),3.12 (m, 2H), 2.54 (s, 3H), 2.35 (m, 2H), 2.18 (m, 2H), 1.59 (d, 3H). MS-APCI (m/z+): 530.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14])[CH3:3].[S:15]([NH2:25])(=[O:24])([C:17]1[CH:22]=[CH:21]C(N)=[CH:19][CH:18]=1)=[O:16]>Cl.C(O)C>[O:14]=[C:6]1[NH:7][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:13]2[C:5]1=[CH:4][NH:2][C:3]1[CH:21]=[CH:22][C:17]([S:15]([NH2:25])(=[O:24])=[O:16])=[CH:18][CH:19]=1
Reactant: CN(C)C=C1C(=O)Nc2cnccc21
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3cnccc32)cc1
Reaction time: 3 h
Yield: 16.8 %

Procedure:
To a 25-ml round-bottom flask was added 0.12 g (0.47 mmol) of 3-dimethylaminomethylene-1,6-diazainden-2(3H)-one, 0.081 g (0.47 mmol) of sulfanilamide, 10 ml of ethanol and two drops of concentrated hydrochloric acid. The reaction mixture was refluxed using an oil bath with stirring for 3 h, then cooled and filtered. The collected solid was dissolved in a minimum volume of hot methanol. Upon cooling, a dark material deposited. The methanol solution was decanted and diluted to twice its volume with ethyl acetate. A light brown solid deposited after standing for 48 h. The solid was isolated by filtration, dried, and redissolved in hot methanol (30 mL). The solution was concentrated to 20 mL and diluted with an equal volume of ethyl acetate. On cooling, a tan solid formed. The solid was isolated by filtration and washed with methanol/ethyl acetate to give 25 mg (17%) of the title compound. 1H NMR (DMSO-d6): δ 7.42 (s, 2H), 7.82 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 8.28 (s, 1H), 8.11 (d, J=6.0 Hz, 1H), 8.38 (d, J=6.0 Hz, 1H), 9.35 (d, J=13.5 Hz, 1H), 11.53 (s, 1H), 11.60 (d, J=13.5 Hz, 1H), 14.6 (br s, 1H); C14H12N4O3S: APCI−MS m/z 315 (M−H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[IH:33]>ClCCl>[IH:33].[F:28][C:25]([F:26])([F:27])[CH2:24][O:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2CCOCC(F)(F)F)CC1
Agent: I
Solvent: ClCCl
Product: O=C(c1nc2ccccc2n1CCOCC(F)(F)F)C1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine (5.0 mmol) and dichloromethane (150 mL). Cool to 0° C. using an ice bath. Add hydriodic acid (gas) until the solution is saturated and stir. After 30 minutes, again add hydriodic acid (gas) until the solution is saturated. After 2 hours, evaporate invacuo to give, after drying, the title compound.
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7](I)=[N:6]1.[Cu][C:22]#[N:23].C(OCC)(=O)C>CS(C)=O>[F:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:14])=[N:12][CH:13]=[C:8]2[C:7]([C:22]#[N:23])=[N:6]1
Reactant: Cc1ncc2c(I)nn(Cc3cccc(F)c3F)c2n1
Reactant: N#C[Cu]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ncc2c(C#N)nn(Cc3cccc(F)c3F)c2n1
Temperature: 150 °C

Procedure:
1.360 g (3.35 mmol) of 1-(2,3-difluorobenzyl)-3-iodo-6-methyl-1H-pyrazolo[3,4-d]pyrimidine and 330 mg (3.68 mmol) of copper(I) cyanide were initially charged in 10 ml of absolute DMSO and the mixture was heated at 150° C. for 2 h. After cooling, the mixture was added to 200 ml of ethyl acetate and washed with a mixture of concentrated aqueous ammonia solution and semisaturated aqueous ammonium chloride solution (v/v=1:3). The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. 1.040 g (purity 92%, 100% of theory) of the target compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=1[O:40][CH3:41]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH:14]3[CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=3[O:40][CH3:41])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCC(=O)Cc1ccc(OCCCBr)c(OC)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(=O)Cc1ccc(OCCCC2CNCCC2c2noc3cc(F)ccc23)c(OC)c1
Yield: 68.7 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]pentanone (3.7 g, 11.3 mmol) in acetonitrile (140 ml) was heated at reflux for 4 hours. At the end of the reaction, the mixture was cooled and filtered. The filtrate was concentrated to an oil. Purification was performed by flash chromatography over a silica gel column (SiO2, 55 g; eluted with 1% methanol in dichloromethane, 600 ml; 3% methanol: 97% dichloromethane, 400 ml). The fractions containing pure product were pooled and concentrated to a solid (4.3 g, 91%). Recrystallization from ethanol (10 ml) gave a powdery solid of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-3-piperidinyl]propoxy]-3-methoxyphenyl]pentanone (3.22 g), m.p.=79°-80° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:17]([NH2:19])=[O:18].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.N1CCCCC1>C(O)C>[CH3:16][N:14]([CH3:15])[C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4]2[C:3]([C:17]([NH2:19])=[O:18])=[C:2]([N:1]=[CH:25][C:24]3[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=3)[NH:6][N:5]=2)=[CH:13][CH:12]=1
Reactant: CN(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)c1ccc(Nc2n[nH]c(N=Cc3ccc(O)cc3)c2C(N)=O)cc1
Yield: 90 %

Procedure:
5-amino-3-((4-(dimethylamino)phenyl)amino)-1H-pyrazole-4-carboxamide (900 mg) was suspended in 10 mL of ethanol and 4-hydroxybenzaldehyde (634 mg, 1.5 eq.) and piperidine (0.25 eq., 89 mL) was added. The reaction was stirred at reflux until the starting material was absent and confirmed by HPLC. After the reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((4-(dimethylamino)phenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide t as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (1.130 g, 90% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:34])[CH2:8][CH2:9][CH:10](Br)[C:11]([CH3:32])=[CH:12][CH:13]([C:23]1[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][C:24]=1[CH3:31])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])(=[O:3])[CH3:2].N12CCCC1=NCCC2>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:34])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:32])[CH:12]=[C:13]([C:23]1[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][C:24]=1[CH3:31])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)CCC(Br)C(C)=CC(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Agent: C1CN=C2CCCN2C1
Solvent: ClCCl
Product: CC(=O)OCC=C(C)CCC=C(C)C=C(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Reaction time: 5 h
Yield: 84.1 %

Procedure:
A 50 ml flask was charged with 1.38 g (2.5 mmoles) of 1-acetoxy-6-bromo-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,7-nonadiene (17) obtained in Example 14, 15 ml of methylene chloride, and 0.6 ml (5 mmoles) of 1,5-diazabicyclo[4.3.0]non-5-ene. The mixture was stirred for 5 hours under reflux. The reaction mixture was worked up by the same operation as in Example 22, to give 0.99 g (yield 84%) of 1-acetoxy-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,6,8-nonatriene (19).