Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@@H:8]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:9][N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=O)=[O:6])[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:55]1([CH2:61][CH2:62][CH2:63][CH2:64][NH2:65])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[C:55]1([CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:12](=[O:14])[C@@H:11]2[CH2:15][CH2:16][CH2:17][N:10]2[CH2:9][C@@H:8]([NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:22])=[O:6])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)O)NC(=O)OC(C)(C)C
Reactant: NCCCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 82 %

Procedure:
Using the procedure described in ample 1e, a solution of 1-[2-(S)-[[(1,1-dimethylethoxy)carbonyl]amino]-4-methylpentyl]-L-proline (200 mg), DCC (197 mg, 0.955 mmol), DMAP (102 mg, 0.83 mmol), HOBT (155 mg, 1.012 mmol), triethylamine (177 uL, 1.27 mmol) in DMF (1.0 mL) and CH2Cl2 (2 mL) was treated with 4-phenylbutylamine (150 uL) to provide 233 mg (82%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][C:13]([CH3:18])=[C:12]([CH3:19])[CH:11]=3)[C:6]=2[CH:20]=1.CN(C)[C:23]1[O:24][C:25](=[O:33])[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=1.C(O)(=O)C.O>C(Cl)Cl.C(OCC)C>[CH3:17][O:16][C:15]1[C:10]([C:7]2[C:6]3[CH:20]=[C:2]([N:1]4[C:25](=[O:33])[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[NH:28][C:23]4=[O:24])[CH:3]=[CH:4][C:5]=3[S:9][N:8]=2)=[CH:11][C:12]([CH3:19])=[C:13]([CH3:18])[CH:14]=1
Reactant: COc1cc(C)c(C)cc1-c1nsc2ccc(N)cc12
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(C)c(C)cc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Yield: 62.4 %

Procedure:
A mixture of 5-amino-3-(6-methoxy-3,4-xylyl)-1,2-benzisothiazole (8.53 g, 30.0 mmol), 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (6.87 g, 33.0 mmol) and acetic acid is refluxed for 2 hours, cooled, and poured into water. The resultant aqueous mixture is filtered to obtain a solid. A solution of the solid in methylene chloride is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and a 5% diethyl ether in methylene chloride solution gives the title product as a yellow foam (8.37 g, 62.0%) which is identified by NMR spectral analyses.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:35][CH2:36][N:31]([C:28]3[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=3)[CH2:32][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: CC(C)c1ccc(N2CCNCC2)cc1
Product: CCc1cc(NC(=O)N2CCN(c3ccc(C(C)C)cc3)CC2)c(OC)nc1C
Yield: 68 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-isopropylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][C:32]([F:40])([F:39])[CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:18][N:19]([S:35]([CH2:34][CH2:33][C:32]([F:40])([F:39])[F:31])(=[O:37])=[O:36])[C:20](=[O:28])[N:21]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)CCC(F)(F)F)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 3,3,3-trifluoropropane-1-sulfonyl chloride to give the title compound as an off-white solid. MS: 539.0 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4](Cl)=[N:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1F.NC(N)=[S:22].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]1[S:22][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:12])[C:6]=2[N:5]=1
Reactant: NC(N)=S
Reactant: Fc1cncc(F)c1N=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Fc1cncc2sc(-c3c(Cl)cccc3Cl)nc12
Temperature: 85 °C
Reaction time: 18 h
Yield: 59.4 %

Procedure:
A stirred suspension of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-benzimidoyl chloride (15.4 g, 47.8 mmol), thiourea (14.5 g, 0.191 mol) and pyridine (19.3 mL, 0.239 mol) in isopropanol (250 mL) was heated at 85° C. for 4 hours under argon. To the mixture was added Et3N (40 mL, 0.287 mol) and heating at 85° C. was continued for 18 hours. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between EtOAc (500 mL) and water (500 mL). The aqueous phase was extracted with EtOAc (300 mL) and the combined organic layers were washed with water, then dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-50% EtOAc in pentane to afford the title compound as a pale yellow solid (8.5 g, 59%). LCMS (Method D): RT=3.56 min, m/z: 299 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].C(N(C(C)C)C(C)C)C>C1COCC1>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:20](=[O:21])[NH:1][C:2]3[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=3)[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CC(=O)Nc1ccc(N)cc1OCc1ccccc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1OCc1ccccc1
Temperature: 80 °C
Yield: 53.6 %

Procedure:
N-(4-Amino-2-benzyloxy-phenyl)-acetamide (419) (3 g, 11.72 mmol) and Fmoc-Cl (3.1 g, 12 mmol) were combined and dissolved in THF (60 mL). iPr2EtN (18 mmol, 1.2 equiv.) was added and the mixture was heated to 80° C. for 15 minutes while stirring. TLC indicated complete reaction at this point. The mixture was poured into ice-water (500 mL) and a white solid precipitated. The solid was collected by filtration under reduced pressure followed by drying under high vacuum to give the desired product (420) as a white powder (3 g, 6.28 mmol, 54% yield). LC-MS (ESI): (exact mass: 478.19) m/e=479.2 [M+1]+ (70%), 957.6 [2M+1]+ (100%).
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:6].[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCOCC1.O>[C:21]([O:20][C:18]([NH:17][C@@H:4]([C@@H:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[CH3:6])[C:3]([OH:25])=[O:2])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H](C)Nc1ccccc1[N+](=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ccccc1[N+](=O)[O-])[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,3S)-2-tert-butoxycarbonylamino-3-(2-nitro-phenylamino)-butyric acid methyl ester (5.71 g, 16.2 mmol) in dioxane water (1:1, 100 ml) was added an aqueous solution of 2.5 M lithium hydroxide (31 ml) and the reaction was stirred at ambient temperature for 2 h. The reaction was made acidic with 10% aqueous citric acid, diluted with water (60 ml) and extracted with ethyl acetate (2×100 mL). The organic layers were combined, washed with water (1×50 mL), brine, dried over sodium sulfate, filtered and concentrated in vacuo to give (2S,3S)-2-tert-butoxycarbonylamino-3-(2-nitro-phenylamino)-butyric acid which was carried to the subsequent step without purification (5.48 g, 99%).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[C:68]([CH3:73])=[N:69][CH:70]=[CH:71][CH:72]=2)[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[C:68]([CH3:73])=[N:69][CH:70]=[CH:71][CH:72]=4)[C:56]=3[CH3:74])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Cc1ncccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ncccc1-c1nc2cc(F)cc(F)c2c(Nc2cc(N3CCOCC3)cnc2N2CCOCC2)c1C

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.053 mmol), 2,5-dimorpholinopyridin-3-amine (0.104 g, 0.39 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline (0.1 g, 0.33 mmol), Pd2dba3 (0.012 g, 0.013 mmol) and sodium tert-butoxide (0.064 g, 0.67 mmol) in toluene (3.3 mL) at 100° C. for 43 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(2-methylpyridin-3-yl)-quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (1H, dd, J=4.9, 2.0 Hz)), 7.76 (1H, m), 7.72 (1H, m), 7.63 (1H, m), 7.55 (1H, d, J=2.5 Hz), 7.50 (1H, m), 7.38 (1H, dd, J=7.4, 4.7 Hz), 6.31 (1H, br. s.), 3.73 (4H, br. s), 3.65 (4H, app t, J=4.5 Hz), 3.17 (2H, br. s), 2.94 (4H, app t, J=4.5 Hz), 2.82 (2H, br. s), 2.29 (3H, s), 1.87 (3H, s). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C:3]([C@@H:5]2[C@:22]3([CH3:23])[C@H:8]([C@H:9]4[C@H:19]([C:20](=[O:24])[CH2:21]3)[C@:17]3([CH3:18])[C@H:12]([CH2:13][C:14](=[O:27])[C:15](=[CH:25]O)[CH2:16]3)[CH2:11][CH2:10]4)[CH2:7][CH2:6]2)([CH3:4])[O:2]1>[Pd].C(OCC)(=O)C>[CH2:29]1[CH2:1][O:2][C:3]([C@@H:5]2[C@:22]3([CH3:23])[C@H:8]([C@H:9]4[C@H:19]([C:20](=[O:24])[CH2:21]3)[C@:17]3([CH3:18])[C@H:12]([CH2:13][C:14](=[O:27])[C@H:15]([CH3:25])[CH2:16]3)[CH2:11][CH2:10]4)[CH2:7][CH2:6]2)([CH3:4])[O:28]1
Reactant: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5CC(=O)C(=CO)C[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C5(C)OCCO5)[C@@]4(C)CC(=O)[C@@H]32)CC1=O
Reaction time: 2 h
Yield: 6 %

Procedure:
A mixture of 20,20-ethylenedioxy-2-hydroxymethylene-5α-pregnane-3,11-dione (6 g.), palladium-on-charcoal (10%, 2.5 g.) and ethyl acetate (250 ml.) was shaken under hydrogen for 51/2 hr. The mixture was then filtered through Kieselguhr and the filtrate was evaporated to dryness (6.1 g.) in vacuo. A portion of the residue (3 g.) was subjected to preparative t.l.c. The less polar fraction (0.59 g.) was crystallised from methanol to give title compound (0.35 g.), m.p. 168°-169°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=2[N:13]=1.[CH2:19]([C@H:21]1[O:23][CH2:22]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:23]1[CH2:22][C@@H:21]1[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[N:13][C:12]=2[CH:14]=1
Reactant: Oc1ccc2oc(-c3ccc(Cl)cc3Cl)nc2c1
Reactant: ClC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ccc(-c2nc3cc(OC[C@H]4CO4)ccc3o2)c(Cl)c1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A mixture of 2-(2,4-dichlorophenyl)benzoxazol-5-ol (6.0 g, 36 mmol), (S)-(+)-epichlorohydrin (3.3 g, 315 mmol) (20 ml, 182 mmol), and potassium carbonate (20 g, 144 mmol) in acetone (100 ml) was heated to reflux and allowed to stir overnight. The solution was allowed to cool and filtered through Celite 512. The filtrate was evaporated under reduced pressure to yield an oil, which was chromatographed on silica gel, eluting with 20% ethyl acetate/hexanes, to yield 5-[((2R)oxiran-2-yl)methoxy]-2-(2,4-dichlorophenyl)benzoxazole as white solid (6.2 g, 28 mmol).
Reaction SMILES: C(OC(=O)[NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:17]=2)=[CH:11][N:10]=1)=S)C.[Cl-].O[NH3+].C([N:38](CC)C(C)C)(C)C.C(O)C>CO>[NH2:38][C:6]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([NH:23][C:24](=[O:25])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH:17]=3)=[CH:11][N:10]2[N:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(F)c(NC(=O)OC(C)(C)C)c2)cn1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)nn3c2)ccc1F
Yield: 83.5 %

Procedure:
In the same manner as in Example 23-1 and using ethyl{[(5-{3-[(tert-butoxycarbonyl)amino]-4-fluorophenoxy}pyridin-2-yl)amino]carbonothioyl}carbamate (13.5 g, 30.0 mmol), hydroxylammonium chloride (14.7 g, 212 mmol), N,N-diisopropylethylamine (26.2 mL, 150 mmol), ethanol (75 mL) and methanol (75 mL) as starting materials, the title compound (9.00 g, 84%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:15]1[CH:20]=[CH:19][C:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>CN(C)C(=O)C>[N:15]1[CH:16]=[CH:17][C:18]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:19][CH:20]=1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccncc2)cc1
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccncc2)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (4.28 g, 30.5 mmol) in N,N-dimethylacetamide (30 mL) was added thionyl chloride (3.63 g, 30.5 mmol) and the mixture stirred at -10° to -15° C. for one hour. 4-(4-Pyridylsulfonyl)benzenamine (4.77 g, 20.4 mmol) was added in one portion and the mixture stirred at room temperature overnight. The solution was poured into water, the yellow solid filtered and purified by flash chromatography (50% v/v ethyl acetate in methylene chloride). Evaporation of the eluent and trituration of the resulting solid with hot methylene chloride yielded the title propanamide (4.61 g, 60%) as an off-white solid; mp 255°-257° C. 1H-NMR (300 MHz, d6 -DMSO): 1.71 (s, 3H, CH3), 7.71 (s, 1H, OH), 8.01 (d, 2H, J=4.5 Hz, aromatic), 8.12 (d, 2H, J=7.1 Hz, aromatic), 8.19 (d, 2H, J=7.1 Hz, aromatic), 9.00 (d, 2H, J=4.5 Hz, aromatic), 10.61 (s, 1H, NH). MS (CI, CH4): 375(M+1).
Reaction SMILES: C[CH:2]1[C:10]2[C:5](=[C:6](OC)[CH:7]=[CH:8][C:9]=2OC)[C:4](=[O:15])[CH2:3]1>C(O)C>[C:4]1(=[O:15])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(OC)c2c1C(=O)CC2C
Solvent: CCO
Product: O=C1CCc2ccccc21

Procedure:
The above-described aromatic composition of the present process is added in an amount of 1 ppm to the material meat of sausages, and this material meat is smoked to make sausges. Likewise, the mixture (in the ratio 2:1) of 3-methyl-4,7-dimethoxyindan-1-one and 3,4-dimethyl-7-hydroxindan-1-one is dissolved in ethanol in an amount of 5 %, and the solution is added to the material meat but in an amount to give 10 ppm by weight of said indanone compounds mixture thereto, and the material is smoked.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](OC)=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[NH2:18][NH2:19]>CCO>[NH2:13][C:12]1[NH:19][N:18]=[C:10]([C:4]2[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([F:1])[CH:3]=2)[C:11]=1[C:14]#[N:15]
Reactant: COC(=C(C#N)C#N)c1cc(F)cc(OC)c1
Reactant: NN
Solvent: CCO
Product: COc1cc(F)cc(-c2n[nH]c(N)c2C#N)c1
Reaction time: 1.5 h

Procedure:
2-((3-fluoro-5-methoxyphenyl)(methoxy)methylene)malononitrile (BA69, 0.029 mol) stirred in EtOH (20 ml) at room temperature under an argon atmosphere. Hydrazine (1.4 ml, 29 mmol) was added and reaction was left stirring for 90 minutes. Reaction mixture was concentrated in vacuo and dried on vacuum pump overnight to yield intermediate 5-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazole-4-carbonitrile (BA73). Formamide (20 ml) was added and reaction was heated to 180° C. under an argon atmosphere overnight. Reaction was cooled and dH2O was added (40 ml) forcing a white precipitate out of solution. Precipitate was collected and washed with dH2O. Solid was dried and purified by silica gel column chromatography [MeOH—CH2Cl2, 10:90] to yield 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA75).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2Cl.[I-:14].[Na+].C(#N)CC.S([O-])([O-])=O.[Na+].[Na+]>C([O-])([O-])=O.[K+].[K+]>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[I:14]
Reactant: Clc1ccnc2ccc(Br)cc12
Reactant: [I-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Solvent: CCC#N
Product: Brc1ccc2nccc(I)c2c1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A 3-neck roundbottom flask equipped with a reflux condenser and mechanical stirrer was charged with 6-bromo-4-chloroquinoline hydrochloride (34.6 g, 0.124 mol), anhydrous sodium iodide (92.93 g, 0.62 mol) and propionitrile (1 L). The resulting slurry was stirred vigorously at reflux for 96 hrs. The solution was cooled to room temperature and 500 mL of 10% K2CO3 solution was added, followed by a 200 mL of a 5% sodium sulfite solution. The reaction mixture was extracted with CH2Cl2 (600 mL×4). The combined organic extracts were dried (Na2SO4), filtered and conc. in vacuo to provide the title compound as an off-white solid (41.8 g, >quantitative yield), which was used without further purification. LCMS [M]+=333.8, 334.8, 336.0 and 337.0; 1H NMR (400 MHz, d-DMSO) δ (ppm)=7.98-7.96 (2 H, m), 8.14-8.16 (1 H, m), 8.23 (1 H, d), 8.53 (1 H, d).
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[CH:6](C3C=CC=CC=3)[NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:4]=2[CH:3]=1.CC(C)=[O:23].Cl([O-])(=O)=O.[K+]>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:18][C:19]=1[CH3:20])[C:6]1=[N:7][CH2:8][CH2:9][N:10]1[CH:11]2[OH:23]
Reactant: CC(C)=O
Reactant: Cc1cc2c(cc1C)C(c1ccccc1)NCCNC2
Agent: [K+]
Agent: [O-][Cl+2]([O-])[O-]
Solvent: O
Product: Cc1cc2c(cc1C)C(O)N1CCN=C21

Procedure:
Four grams of 1,2,3,4,5,6-hexahydro-8,9-dimethyl1-phenyl-2,5-benzodiazocine is dissolved in 100 ml. of acetone. A solution of 2 g. of potassium chlorate in 100 ml. of water is added dropwise over a period of an hour. Thereafter, the mixture is filtered and evaporated to dryness to afford 2,3-dihydro-7,8-dimethyl-5H-imidazo[2,1-a]isoindol-5-ol which is recrystallized from methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH2:15]OS(C)(=O)=O)[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:22].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH2:15][F:22])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCc2ccccc2)co1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=c1cc(CF)occ1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice/salt cooled solution of the sulfonate ester obtained in step 1 above ester (20.0 g, 64.4 mmol) in acetonitrile (120 mL) was added a mixture of a 75 wt % solution of tetrabutylammonium fluoride (35 g, 96.6 mmol) and 40 mL of acetonitrile. Additional tetrabutylammonium fluoride solution (35 g, 96.6 mmol) was added after 2.5 hrs and the reaction mixture was allowed to stir at room temperature for overnight. The reaction was concentrated in vacuo to give a dark red oil. The residue was diluted with 700 mL of ethyl acetate and washed 5 times with 120 mL of a 10% sodium hydrogen carbonate solution and twice with 120 mL of brine. The organic layer was dried over sodium sulfate, and concentrated to give a dark red oil. The crude product was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexanes (1/1, v/v) as the eluant to give 5-benzyloxy-2-fluoromethyl-pyran-4-one as a waxy-like solid (10.0 g, 66% yield). 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.69 (s, 1H), 7.42-7.37 (m, 5H, H—Ar)), 6.57 (s, 1H), 5.36 (d, J=46.5 Hz, 2H, CFH2), 4.97 (m, 2H, OCH2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH2:18][CH3:19])=[C:16]([C:20](OC)=[O:21])[C:15]([CH2:24][CH3:25])=[N:14]1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([CH2:18][CH3:19])=[C:16]([CH2:20][OH:21])[C:15]([CH2:24][CH3:25])=[N:14]1
Reactant: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of 8 g (20 mmol) of the compound of step B in 50 mL of tetrahydrofuran (THF) was treated at 0° C. with 44.1 mL of 1.5 M diisobutylaluminum hydride in toluene solution over a period of 5 minutes. The reaction was stirred for 2 hours at 0° C. and was then cautiously quenched with water. The product was extracted into ethyl acetate and dried and evaporated to give the title compound in 46% yield. 1H-NMR (CDCl3) δ 1.04 (3H, t, J=7), 1.26 (3H, t, J=7), 2.44 (2H, q, J=7), 2.70 (2H, q, J=7), 4.54 (2H, s), 7.66 (2H, s).